Bull. Org. mond. Sante 1963, Bull. WldHlth Org. 29, 7-41

On the Origin of the Human Treponematoses (Pinta, Yaws, Endemic Syphilis and Venereal Syphilis)

C. J. HACKETT, M.D., F.R.C.P.1

A close relationship between the four human treponematoses is suggested by their clinical and epidemiological characteristics and by such limited knowledge ofthe treponemes as there is at present. No treponeme of this group (exceptfor that of the rabbit) is known other than in man, but the human treponemesprobably arose long agofrom an animalinfection. The long period cfinfectiousness ofpinta suggests that it may have been the earliest human treponematosis. It may have been spread throughout the world by about 15 000 B.C., being subsequently isolated in the Americas when the Bering Strait wasflooded. About 10 000 B.C. in the Afro-Asian land mass environmental conditions might have favoured treponeme mutants leading to yaws; from these, about 7000 B.C., endemic syphilis perhaps developed, to give rise to venereal syphilis about 3000 B.C. in south-west Asia as big cities developed there. Towards the end of the fifteenth century A.D. a further mutation may have resulted in a more severe venereal syphilis in Europe which, with European exploration and geo- graphical expansion, was subsequently carried throughout the then treponemally uncom- mitted world. These suggestions find some tentative support in climatic changes which might have influenced the selection of those treponemes which still survive in humid or arid climates. Venereal transmission would presumably remove the treponeme from the direct influence of climate. The author makes a plea for further investigation of many aspects of this subject while this is still possible.

CONTENTS

THE DISEASES ...... 8 EVOLUTION OF THE TREPONEMATOSES ...... 21 The human treponematoses ...... 8 Origin of human infections ...... 21 Course of the human treponematoses . . . . . 10 Infectious contacts in man ...... 22 Pathological characteristics of the human tre- Size of community needed to maintain infections 22

ponematoses ...... 14 ORIGIN OF THE HUMAN TREPONEMATOSES . . . . . 23 Prevalence of the human treponematoses . . . 14 Geographical distribution of the human trepone- Step 1-Pinta ...... 24 matoses ...... 15 Step 2-Yaws ...... 26

Animal treponematoses ...... 18 Step 3-Endemic syphilis ...... 27

Step 4-Venereal syphilis ...... 28

THE CAUSAL ORGANISMS ...... 18 CONCLUSION ...... 30 The pallidum/pertenue treponemes ...... 18 Site of entry and transmission of the treponemes 19 RisUM1 ...... 38 Other treponemes in man and nature . . . . 21 REFERENCES ...... 39

I Senior Medical Officer, Research Planning and Co-ordination, World Health Organization, Geneva, Switzerland. 1274 -7- 8 C. J. HACKETT

The human treponematoses comprise four closely- a long period of infectiousness and is geographically related infections: pinta (mal del pinto, carate), isolated in the Americas from the other treponema- yaws (pian, framboesia, bouba), endemic syphilis toses. Its causal organism, Treponema carateum, is (bejel), and venereal syphilis. More information the only one of the four treponemes with which is needed before their origins can be traced with animals have not yet been infected experimentally. confidence. However, consideration of this interest- These characteristics distinguish pinta from the other ing question may indicate relevant studies to pursue. three treponematoses. The first four sections of this paper summarize The other subgroup contains yaws and endemic various aspects of the problem and the fifth contains syphilis. These, like pinta, are diseases of less- some suggestions based upon existing knowledge developed rural populations and are usually con- and reasonable assumptions.' tracted in childhood. Between yaws and endemic It is hoped that this brief survey will stimulate syphilis are certain clinical and epidemiological constructive action while this is still possible. differences. Typically, endemic syphillis occurs in warm, semi-arid and arid areas and yaws in warm THE DISEASES countries with higher rainfall and more vegetation. As a rule, neither of them is endemic in urban popu- The human treponematoses lations nor do both occur in the same population The four treponematoses in man are caused by (see page 12). In both, poor standards of hygiene organisms which are microscopically indistinguish- are important. able by present techniques. The appearance of the There is little need here to describe the venereal Treponema pallidum, which Schaudinn in 1905 des- disease of urban populations in any climate, syphilis. cribed from the lesions of venereal syphilis, is typical It,was, until recently, a serious public health problem of them. of advanced countries and caused much suffering These four human treponematoses 2 may be and disability (see page 13). The severe late lesions grouped according to the usual way they are trans- of the heart, nervous system and eye appear to mitted, as follows: differentiate venereal syphilis from the non-venereal (1) Non-venereal (often called endemic) trepone- treponematoses (Table 1). However, the frequency matoses; transmitted mostly among children: of these lesions in venereal syphilis in Africa in the Pinta past was thought to be low, but Limbos (1957) com- (a) ments upon the occurrence of central nervous system (b) Yaws involvement in syphilis there. Endemic 3 syphilis The pattern of venereal disease in Africa may have (2) Venereal (sometimes called sporadic) trepone- changed in the last 15 years. Many of the present matosis; transmitted mostly among adolescents inhabitants of large African cities have come from and adults: the country, where they might have had yaws in Venereal or sporadic syphilis. childhood. The seroreactor rate in urban primiparae In the first group are two subgroups. One consists in several tropical African countries is about 20%, of pinta, which has different clinical manifestations, but congenital syphilis is often infrequent. This may be because childhood yaws protects against adult 1 Much help has been received from the constructive infection with venereal syphilis. However, in Dakar, criticism of many friends during the past four years. which is just north of the yaws area, Senecal et 2 In this paper each of the four treponemes and the four diseases related to them are regarded as different entities. al. (1962) have reported 10 %-15y% seroreactors Hudson (1946, 1958) has, however, strongly contended among pregnant women and estimated 20% con- that all the treponemal infections comprise one disease, treponematosis, which is caused by one treponeme, T. palli- genital syphilis among children. They also found dum, " which presents different clinical patterns under that about 11 0 of children born of seroreactive different climatic and sociological conditions". mothers who were not treated during the pregnancy 3Since the name " endemic syphilis " still causes con- fusion because the significance of the " endemic " is often were also seroreactive with or without clinical signs. missed, another name for this disease is needed. Local Intra-uterine transmission in venereal syphilis and names, such as bejel, are not suitable. In general, endemic syphilis is a treponematosis of arid areas and thus the name its absence in the endemic treponematoses are per- " treponaridosis " might be suggested because it is the haps not important in the differentiation of those treponematosis of arid countries. Were a new name needed for yaws, which it is not, the name "treponumidosis" might diseases because in venereal syphilis this transmission be proposed. is also unusual when the mother has been infected ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 9 for more than five years. However, women with historians is to know how soon venereal syphilis may florid early infectious yaws have been reported to enter such populations when the indigenous endemic have borne healthy children (Baermann, 1911). treponematosis has been eradicated. The unlikelihood of venereal syphilis occurring in The differentiation of venereal syphilis and yaws populations infected in childhood with yaws or has been discussed by Stannus (1926, 1936), Black- endemic syphilis casts doubt upon early reports of lock (1932a, 1932b), Turner (1937) and Turner & venereal syphilis in populations later found to have Hollander (1957). The solution of this problem high prevalences of these diseases. This must be kept must await the fuller study of the antigenic constitu- in mind in interpreting such reports in relation to tion of the treponemes. historical medical geography. A growing problem Some clinical characteristics of these four infec- for present public health workers and future medical tions are listed in Table 1.

TABLE I SOME CLINICAL CHARACTERS OF THE TREPONEMATOSES

Character Pinta 1 Yaws Endemic | Venereal ~~~~syphilis~~ ~~s yphilis Usual source of treponemes Skin anywhere Skin anywhere Buccal mucosa Genital and mucosal lesions

Size of infectious area Large Large Small Small

Duration of: Infectiousness of individual lesions Many years A few months A few months A few months Infectiousness of patients, including infectious relapses Many years 3-5 years 3-5 years 3-5 years

Latency f Absent Characteristic Characteristic Characteristic

Lesions: Initial, site Exposed skin Skin of legs Mouth ? Genital Initial, occurrence Infrequent Frequent Unusual Frequent Generalized skin, extent Extensive Extensive Limited Moderate Genital, occurrence Unusual Scanty Scanty Frequent Buccal mucosal, occurrence Absent Scanty or absent Moderate Scanty Palmar and plantar hyperkeratoses, occurrence Absent b Frequent Scanty c Scanty Bone, occurrence Absent Moderate Moderate Scanty Juxta-articular nodules, occurrence Absent Frequent Scanty Scanty Heart, brain and other viscera, occurrence Absent Absent d Scanty and mild, Moderate or absent

Congenital transmission Absent Absent Absent Present

Age-group of most infections Children Children J Children Adults

a Latency In a communicable disease is a stage in its course in which there is evidence of infection such as seroreactivity but no clinically detectable active lesions. b Hyperkeratoses have been attributed to pinta in Cuba. However, there may have been confusion with hyperkeratoses of yaws. c Many of the hyperkeratoses illustrated by Hudson (1936) and Murray et al. (1956) are not due to endemic syphilis (Hackett & Loewenthal, 1960). d Weller (1937) reports lesions resembling those of venereal syphilis from supposed yaws cases In Haiti; he found no venereal syphilitic lesions of the brain in them. 10 C. J. HACKETT

The comparison of yaws or endemic syphilis with Fournier (1903) found that of 642 extra-genital acquired sporadic syphilis contracted non-venereally chancres in venereal syphilis, 484 occurred on the by children from adults with infectious venereal head, and that of these, 435 occurred on or in the syphilis would be more correct than the comparison mouth (328 on the lips). He reports that probably of either with venereal syphilis contracted venereally about 10% of chancres were extra-genital. by adults. Jeans & Cooke (1930), in a careful study Where endemic syphilis is reported out of its of 34 cases, say that the manifestations of this " pre- characteristic arid climatic range, as in Yugoslavia pubescent syphilis " are those of acquired syphilis in and Uganda, there is a possibility that it is, or has adults, except that mucous membrane lesions and originated from, non-venereally acquired sporadic condylomata are more frequent and the Wassermann syphilis in children. However, the studies of Turner reaction more readily reversible. Other reports of & Hollander (1957) on the treponemes do not sup- juvenile syphilis (Eisenberg et al., 1949; Taylor, 1954; port these suggestions because the Bosnian endemic Rajam et al., 1955) support these findings. Gron syphilis treponemes differed from the treponemes of (1928) does not clearly distinguish between endemic venereal syphilis. syphilis and non-venereally acquired sporadic syphi- Dr E. I. Grin, of Sarajevo, Yugoslavia, (personal lis of children. Many of the outbreaks to which he communication, 1962) has observed among children refers were clearly of the latter infection and some small outbreaks of non-venereally acquired sporadic may have been of yaws. syphilis which had all the characteristics of endemic Endemic syphilis is a non-venereal disease of rural syphilis, arising from an adult with infectious vene- children in warm, dry climates,' neither derived from, real syphilis. However, he pointed out that the nor associated with, venereal syphilis in the com- Bosnian endemic syphilis was probably brought from munity. The late cardiac and cerebral manifestations a long-standing focus in Anatolia during the Turkish of venereal syphilis, 'which are typically severe in occupation which commenced in the fifteenth cen- that disease, do not occur in endemic syphilis or are tury. Perhaps this present-day Bosnian treponema- scanty and mild. This and its rural occurrence are tosis indicates an aspect of the pattern of the tre- perhaps distinguishing characters. Initial lesions are ponematoses before the last decade of the fifteenth regarded as unusual. The early lesions are more century. Similar outbreaks of non-venereally ac-- frequent in children than in adults. quired sporadic syphilis in childhood originating Non-venereally acquired sporadic syphilis in from infectious venereal syphilis in adults acquired in children is mainly an urban disease in any climate towns may occur in rural areas in other countries and originates from simple contact with infectious where the standards of personal hygiene are low. venereal syphilis in adults or through contaminated A number of diseases such as sivvens and other objects. Thus non-venereally acquired sporadic so-called syphiloids occurred in Europe and else- syphilis and venereal syphilis are present in the com- where in the seventeenth and eighteenth centuries. munity and perhaps in the same family at the same which are thought to be treponematoses (Swediaur, time. Transmission among children may follow 1821). Attempts have been made to diagnose these infection of children from adults and children may conditions more accurately (Pollock, 1953). The infect adults, but the epidemiological pattern is that possibility that they were non-venereally acquired of venereal syphilis with incidental infection of sporadic syphilis should be considered. children. Initial lesions are infrequent (Eisenberg et al., 1949; Rajam et al., 1955). However, Tucker & Course of the human treponematoses Mulheim (1948) report that over a third of extra- The course of venereal syphilis in man might be~ genital chancres in children were in the buccal cavity. taken as typical of that of the treponematoses be-- This non-venereally acquired sporadic syphilis in cause in it may occur all the manifestations of children gives rise to all the severe late manifesta- endemic syphilis and yaws and because it has been tions of venereal syphilis. This and its urban and intensively studied (Gjestland, 1955). The following often familial incidence are perhaps distinguishing description is a composite picture of the treponema- characters. Early lesions in adults are frequent and toses. are usually due to venereal infections. The treponeme enters the body through the mucosa or through a break in the epidermis. Animal 'Often the dryness may be modified by proximity of experiments indicate that this penetration may take villages to marshes or rivers. only a few minutes but the longest time that may be: ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 1I taken is not known, although such knowledge would enter the skin and multiply there to produce the have considerable practical value. Treponemes papillomata. In these lesions the treponemes con- divide by transverse division about every 30 hours tinue to multiply until interrupted by the immune (Turner & Hollander, 1957). processes of the body or by some extraneous factor, Magnuson et al. (1956), from the results of the such as treatment (Turner & Hollander, 1957). As inoculation of known numbers of virulent T. pal- the immune response increases the lesions heal but lidum into non-syphilitic male volunteers and into some treponemes persist through the latent stage 12 rabbits, calculated that the 50% infectious dose that follows. Later, when treponemes again multiply, was less than 57 treponemes. As few as 10 trepo- a relapse occurs. This migration occurs in experi- nemes produced generalized infection with papular mental infections in animals (Eagle, 1948). The initial lesions but these developed more slowly than early generalized skin eruption appears some weeks after larger doses which more often ulcerated. One after infection. Fenner (1950) showed that in ectro- thousand to 10 000 treponemes consistently pro- melia (a virus infection of mice) during a first blood duced lesions with an incubation of 19 days, which infection, the virus enters the bone-marrow or other is about that of sexually acquired syphilis. tissues where multiplication takes place. This is Infection in animals has followed the inoculation followed by another blood-stream infection by virus of two treponemes and of material in which tre- which gives riEe to the generalized skin lesions. ponemes were too few to be found microscopically Schcbl (1928) believed, from his experimental yaws (Schobl, 1928; Magnuson et al., 1948; Turner & infections in monkeys, that generalized lesions were Hollander, 1957). Magnuson et al. (1948) also sug- due to treponemes coming frcm the skin. gest that in man " one to two organisms may suffice The initial lesions of yaws and pinta may appear to cause infection once they have passed through the on any exposed part of the skin but in yaws they are epithelial layers of the skin or mucous membranes ". most frequent below the knee (Hackett, 1957b); in Gladstone & van Heyningen (1962) state that endemic syphilis they are said to be infrequent and " Treponema pallidum is one of the most invasive have been thought not to occur, while in venereal organisms known ,.1 syphilis they are usually genital (see page 10). Turner & Hollander (1957) found that the intra- The characteristic early skin eruption of yaws dermal inoculation of 500 T. pallidum (Nichol's (Hackett, 1957a) consists of numerous, usually dis- strain) in rabbits was followed by an incubation crete, proliferative papillomata, moist with exudate period of 17 days. Each tenfold increase or decrease containing numerous infective treponemes. The in the number of treponemes shortened or lengthened early skin lesions of venereal syphilis are dry macules the incubation period by four to five days. They or papules as well as moist condylomata about the estimated that a single treponeme would produce genitalia, axillae, etc. Yaws papillomata in these about 100 million organisms, which they believe are places, especially in adults, may resemble syphilitic needed to produce a visible lesion, in 32 days. The condylomata. In endemic syphilis the early skin number of treponemes involved in natural transmis- lesions are mucous papules, circinate papules and sion in man needs further study. condylomata. Where the treponemes enter the skin they multiply The initial and early lesions of pinta are spreading, and the dermal and epidermal tissues react by cel- scaly plaques of various sizes to which are added lular proliferation and infiltration to produce the after a few weeks bluish pigmentary changes initial lesion. From infection to initial lesion is elsewhere in the skin. Some years later these dys- about three weeks, depending upon the criterion of pigmented areas become depigmented, especially on size of the initial lesion. Initial lesions on healing the hands and feet, although both types of lesion can leave little or no scar unless secondary bacterial be present at the same time. The initial lesions are infection has previously caused destruction. not frequently seen. The plaques usually, and the While the initial lesion is developing, treponemes dyspigmentation sometimes, precede the develop- reach the neighbouring lyrrph glands, which become ment of seroreactivity. Condylomata and hyper- enlarged; some time later treponemes enter the keratoses do not occur. blood-stream and are carried throughout the body, All these early generalized skin lesions start from treponemes reaching the surface of the body by the I Burnet (1962) has said that in endemic diseases infection is most frequent in childhood and that the greater the ease blood-stream. In endemic syphilis, yaws and vene- of transmission the younger will be the age of transmission. real syphilis, the treponemes presumably reach the 12 C. J. HACKETT skin in the capillaries beneath the epidermis, are experimental infections and reinfections in Philippine held up and escape through the capillary walls into monkeys which was reported in detail by Schobl the surrounding tissues. Their multiplication is (1928). The initial lesion may heal and not be fol- accompanied by dermal and epidermal proliferation lowed by any other lesions; it may be followed by and by inflammatory cells which may be influenced an early eruption of papillomata with no subsequent by the temperature and condition of the skin. late lesions; or it may persist for a long time and, At least in some countries in the humid geographi- without a papillomatous eruption, be followed by cal areas, in which yaws typically occurs, papillomata late ulcerated lesions. Schobl (1928) showed that are more frequent in the rainy, humid but cool immunity to the treponeme of yaws was manifest in season than in the dry, warm season (Hackett, 1951). three ways; (a) resistance to superinfection, (b) resist- In the arid geographical areas of endemic syphilis, ance to the generalization of yaws lesions, and the skin is dry and the cellular proliferation of the (c) modification of the yaws lesions that developed. lesions is less marked; the skin lesions of the later A characteristic of the earliest lesions of endemic early (secondary) stage may extend as a thread-like, syphilis is the relatively more frequent occurrence of annular thickening which may enclose a large area papules on the buccal mucosa than in any other of healthy skin (Luger, 1958; Murray et al., 1956). treponematosis (Hudson, 1937). Some of these In these countries, while the summer is hot the winter lesions when they are single and associated with is cold, but the former is longer. Nothing is known unilateral lymphadenitis may be initial lesions of the seasonal variations of prevalence of skin (Luger, 1958). Buccal mucosal lesions have been lesions in endemic syphilis. observed in Uganda in 6 % of 150 yaws patients with Ramsay (1925, 1927) in Assam and Lopez-Rizal papillomata (Hackett, 1939, 1946, 1951). However, & Sellards (1926) in the Philippines have reported careful observers in Java, Thailand and Brazil have the anatomical restriction of generalized early yaws unsuccessfully sought such lesions. The Lango lesions (papillomata) to the mouth, nose and moist district in Uganda, where these mucosal lesions folds of the body (gluteal cleft, axilla, etc.) in moun- were seen, consists of woodland savanna. The tain dwellers where the climate is cool and the wider northern endemic syphilis zone of Africa (see Map 1) anatomical dispersion of these lesions in yaws in Sudan is only about a hundred miles north of patients at lower, warmer altitudes. Ramsay ob- Lango. Grin (1961) reports on the occurrence of served this change in mountain-dwelling patients yaws and endemic syphilis in southern Sudan and who moved down to the humid plains. He states speaks of the " mixture of endemic infections in " the cold weather lesions of yaws are indistinguish- one locality and even in one individual ". However, able from those of syphilis ". It would be interesting he does not define these diseases beyond indicating to confirm these observations. However, other fac- that the diagnosis of yaws depended upon " typical tors may in part be responsible, especially nutri- skin papillomata" and of endemic syphilis upon tional deficiencies (Platt, 1958), and .the influence of " oral mucous plaques and papules in the genital climate on the skin lesions needs further study. region ". The role of humid warmth in the transmission of He refers to patients who, as he says, " pose a yaws was shown in an outbreak among South number of interesting clinical and epidemiological African miners working 2000 m underground; the problems ": infection did not spread to contacts above ground (Hackett, 1953, p. 159). "One of the cases of endemic syphilis was a young girl Goundou 1 (Botreau-Roussel, 1925) is frequent in who had on her neck a large papillomatous lesion which resembled a mother yaw. Furthermore, she had mucous yaws patients in Africa and it responds well to treat- oral plaques with swollen indurated submaxillary lymph- ment in its early stage. However, its extreme scarcity nodes and papillomatous lesions of the genitalia (virgo or absence in other yaws areas raises doubts that it intacta). " is due to yaws despite its apparent response to neoarsphenamine (Hackett, 1951). The diagnosis of such patients must depend Hasselmann (1931) and Schobl & Hasselmann largely upon the criteria used. Perhaps, however, in (1932) have summarized the course of yaws in this epidemiological fringe area there is a treponema- tosis with the characters of both yaws and endemic X Goundou is a usually bilateral bony enlargement of the syphilis, or both diseases may be present in the same nasal processes of the maxilla. community, as Grin suggests. ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 13

Future study of treponemes may reveal the rela- diseases but the late lesions are non-infectious com- tionship between these Uganda and Sudanese T. pared with the early ones. pertenue of yaws and the T. pallidum of endemic Luger & Schmid (1961), from their experience in syphilis. Treponemes from both these areas should Syria 1 and a review of the literature, believe that in be collected in readiness for improved methods of endemic syphilis childhood infections and early treponeme study. repeated superinfections in childhood, with small It would be interesting to transport some children numbers of treponemes which cause no lesion at the recently infected with endemic syphilis to a humid site of entry, result in a few years in the immuno- area and to move some others recently infected with logical protection of the heart and central nervous yaws to a semi-arid or arid area and observe the system. This is in contrast to adult infection and less courses of the diseases. Perhaps such infections, frequent superinfection in venereal syphilis. In this incidentally transported, have already been observed way they account for the rarity, mildness (often only but not reported. It might be impracticable to ob- cerebrospinal fluid changes) or absence of late neuro- serve experimental infections with each treponeme syphilis and cardiovascular lesions in rural popula- in volunteers in the geographical area of the other. tions in whom endemic syphilis is prevalent. Grin The differences in clinical manifestations of the (1953) had arrived at similar conclusions. On the various treponematoses are probably due to the other hand, early infection (Guthe & Luger, 1957; treponeme strains themselves although Hudson Grin, 1953) is said to produce a state of allergy, (1946) does not accept this. especially in the skin, to the treponemes so that later The lesions of the four treponematoses may be superinfection may be followed by destructive lesions summarized as follows: such as gummata. These conclusions are not gene- rally accepted. Symptomless superinfections have Pinta. Continuing activity of early lesions, either been observed in experimental infection in animals, from extension of lesions or from blood-borne but only as a stage in the development of more com- treponemes; the presence of treponemes in lesions plete immunity (Magnuson & Rosenau, 1948; see for many years until the lesions become inactive also Magnuson et al., 1956; and page 11 above). and depigmented (Marquez et al., 1955); the ab- Akrawi (1949) reports two successful experimental sence of latency (Edmundson et al., 1953). The infections in five volunteers under " natural " con- long period of, perhaps not great, infectiousness ditions of endemiz syphilis, as indicated by the is unique among the treponematoses. Palmar change from non-reactivity to reactivity to the or plantar lesions are absent and there are no Wassermann test in the serum. In them no initial bone lesions or late destructive lesions. lesions developed because, he inferred, very few treponemes were present in the inocula. When more Endemic syphilis and yaws. Early stages: skin, treponemes were present initial lesions developed. palmar and plantar lesions; bone lesions. Late These findings need confirmation. stages: destructive skin and bone lesions. Malaria infection in childhood followed by early Venereal syphilis. Early stages: skin lesions; bone and repeated superinfection certainly reduces the lesions not frequent. Late stages: destructive skin, severity of falciparum malaria in adults in hyper- bone and other tissue lesions, and lesions of heart endemic areas, but the early infections themselves and brain. are very severe. However, if the superinfection of the adults ceases, the protection decreases. In the last three infections, treponemes are micro- How many people infected with an endemic scopically scanty or absent in lesions developing three treponematosis (pinta excluded) suffer no serious to five years after infection, when early lesions are disability is uncertain because where patients are unusual; latency and relapses are characteristic of not treated there are no competent observers. How- all stages. ever, Gjestland (1955) from a study of untreated Latency and relapses, occasionally some years after venereal syphilis of about 50 years' average duration the original infection, may favour high prevalence assumed " that somewhere between 60 and 70, and and maintenance in small populations by the dis- probably closer to 60 than 70, out of every 100 un- persal of apparently healthy individuals whose later infectious relapses disseminate the infection. Latency 1 In the same area Hudson (1958) started his studies on and relapses also occur in the late stage of these bejel in 1924.

2 14 C. J. HACKETT treated syphilitics went through life with little or no The differences reported in the histopathological inconvenience as a result of the disease ".1 reactions to these treponemes appear to be more of In yaws and endemic syphilis perhaps about the quantity than of quality. The changes consist of same number also escape serious consequences. perivascular infiltration by leucocytes, lymphocytes and plasma cells with or without endothelial pro- Pathological characteristics of the human treponema- liferation. Ferris & Turner (1937, 1938) and Turner toses & Hollander (1957) conclude that " histologic criteria for the differentiation of the cutaneous and The organs characteristically affected in the subcutaneous lesions of yaws and syphilis are in treponematoses are indicated in Table 2. general unreliable ". In other words, the typical early lesions of yaws and syphilis may be dis- TABLE 2 tinguishable, but if they are not typical then dis- ORGANS CHARACTERISTICALLY AFFECTED tinction may be difficult. Differences in late lesions IN THE TREPONEMATOSES are more difficult to recognize than those in early lesions. However, Hallenberger (1916) maintained Pinta 1 Yaws esyphilis Venereal syphilis that the characteristic vascular changes of syphilis are absent in early and late yaws, but Furtado (1955) found these vascular changes in late yaws. Adequate Skin Skin Skin Skin comparable studies are needed. Hasselmann (1957) Mucosa Mucosa Mucosa has written about " comparative studies on the Central nervous histopathology of syphilis, yaws and pinta ". How- system ever, he deals mainly with the early skin lesions and Bone a Bone Bone he gives no indication of the number of lesions upon Heart and arteries which his descriptions are based. Prevalence of the human treponematoses a Hasselmann (1931), because of the absence of bone lesions in experimental Infections in animals, doubts this In most countries at present the endemic trepone- occurrence in man, except as an extension from skin lesions, as in gangosa. matoses (yaws: Hackett, 1959, 1960; endemic syphi- lis: Luger, 1958) and venereal syphilis are in reces- All four treponemes almost certainly become sion compared with a generation ago, and their prevalences now are of little value in obtaining a blood-borne early in the infection and thus reach all " the tissues of the body. However, the treponemes of picture of each disease in its " wild state. From syphilis cause lesions in tissues not known to be the information available the following prevalences affected by the others. The work of Turner & of endemic treponematoses might be expected in Hollander (1957) suggests that different temperature populations where conditions favour their spread: preferences of treponemes may influence organ pre- Seroreactors . . . . 60%-80% ferences. These may also be related to the occur- Susceptibles . . . . 40%-20 % rence of congenital infection in syphilis. Silverstein Total active clinical . 20% (1962) has suggested that the usual appearance of Infectious lesions . . 2 %-4 % lesions of congenital syphilis at about the sixth month of pregnancy may be more related to the In pinta the total prevalence of clinically active "maturation of foetal ability to respond to the disease would approach that of the seroreactors, stimulus with differentiation of immunologically which might be as high as 80% because latency active cells" than to the passage of the treponemes apparently does not occur (Marquez et al., 1955). through the placenta. In some villages in an endemic syphilis area in Senegal, Senecal et al. (1962) have reported pre- 1 From the study of about a thousand patients untreated valences of seroreactors of 9200 and of clinically for the early manifestations of venereal syphilis contracted from 1891 to 1910, Gjestland (1955) found the following active cases of 4 %. In venereal syphilis in favourable prevalences of subsequent manifestations: clinical secondary and primitive conditions seroreactor rates of relapses, 23.6 %; benign tertiary syphilis, 15.8 %; neuro- 10 syphilis, 6.5%; cardiovascular syphilis, 10.4%. Syphilis 500%-60% and active lesion rates of 6%- % was the primary cause of death in 10.8 %. of the population have been found. Although ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 15 some non-venereal transmission may occur under raes & Roderigues, 1948), while yaws occurs in the these conditions, it does not appear to be frequent Caribbean Islands and on the western and eastern because seroreactors among children may be coasts of South America south to Peru and Rio de few. However, among adults in developed coun- Janeiro. Perhaps pinta survives only where there is a tries seroreactor rates of 10%-30%, depending considerable Amerindian population. This distribu- upon the sector of the community surveyed, were tion of yaws agrees with its importation with slaves usual before the introduction of penicillin (McElli- from Africa during the sixteenth to nineteenth cen- gott, 1960; Hill & Mugge, 1954). The high infecti- turies, although Scott (1943) says that " yaws was ousness of the early lesions of the treponematoses is probably autochthonous in Hispaniola, Brazil, Fiji, emphasized by these prevalences. Samoa and West Africa, and imported into the West Indies by slaves ". However, he had earlier said Geographical distribution of the human treponema- (Scott, 1939) that " it can be affirmed almost with toses certainty that slaves introduced leprosy ... yaws. . . " The general introduction of arsenical and bismuth into the Americas, where " they fell ready victims to preparations about 1920 (although mercury had been diseases already present there notably tuberculosis used at least as early as the fifteenth century) and of and, next to that, syphilis ". Castellani (1908, p. 618), penicillin after 1945, together with stand- however, refers to authors in the second half of the improved seventeenth century who reported that yaws in the ards of living, have greatly reduced the prevalence of " the treponematoses during the past 20 years. The West Indies occurs frequently among the natives improvement in standards of living of the world's (Caribs) who call it pyans or yaya ". This would not population up to the end of the nineteenth century have been expected if they had originally been in- was smaller and much less extensive than that which fected with pinta and had continued so (see page 19). has occurred the However, nearly a century and a half of African during present century. Therefore, slavery may by then have changed the pattern of the geographical distribution of the treponematoses On the about 1900 might be of value in attempting to trace disease. other hand, the statements that the their origin. populations were Carib may not have been ethni- The prevalence of early and late clinical manifesta- cally correct because one of the original purposes tions and of seroreactors in different in of the importation of slaves from Africa was to age-groups a replace the rapidly dying out indigenous population. community provides reliable epidemiological in- " formation. Thus few or no clinical manifestations Hume (1744) said that yaws was endemical in in the population and many seroreactors in adults Guinea and the hotter climates in Africa ". Nicholls are an indication of the recession of the infection (1899) made the interesting observation that Indians during the previous generation. While early clinical arriving in the West Indies were susceptible to yaws. manifestations of treponematoses are the result of S. mansoni bilharziasis probably arrived in the recent infection, reactive sera in older people are due southern parts of the American continent with slaves but leprosy is thought to have arrived there earlier to more distant infection (Hackett, 1960). Thus with such serological and clinical data indicate the reces- Europeans (Scott, 1943). sion or progress that may have occurred in the past Pinta is the ancient endemic treponematosis of the generation. Americas (Guimaraes & Roderigues, 1948; Sanchez When a map of the approximate distribution of et al., 1961). However, occasionally a not identical the treponematoses at the beginning of this century depigmentation of unknown origin (Hackett & (Map 1) 1 is scanned from west to east, several Loewenthal, 1960) occurs in some yaws endemic interesting points may be seen. areas in other parts of the world, but the pattern of In the Americas a block of pinta extends from depigmentation on the palms and wrists may re- Mexico down to the upper Amazon basin (Guima- semble that of pinta (Castello & Castafnedo, 1952; Herrejon, 1938). I The maps attempt to show the distribution of pinta, Such depigmentations in Australian aborigines are yaws and endemic syphilis in the indigenous populations, said to be scanty or absent (Professor J. B. Cleland, except for yaws in the Americas. The distribution of venereal syphilis is that where other treponematoses are absent. Adelaide-personal communication, 1961), although No account is taken of syphilis in cities and towns and its Basedow (1932) writes that " white or pinkish patches extension therefrom into areas where another treponema- tosis might reasonably be expected to have been the earlier appear which may increase in size and coalesce". infection. The maps appear on pages 31 to 37. This occurred most frequently on the backs of the 16 C. J. HACKETT hands but he says it was quite distinct from the extends south-east through Burma, Thailand, depigmented patches in syphilis and leprosy. Cleland Malaya and Indonesia to New Guinea and the (1928) refers to a report of " mottling of the skin Philippines without interruption, and thence into from extensive eczema of the palms and soles" in the scattered Pacific islands, where it was present aborigines of the Northern Territory of Australia when the first European explorers arrived (Buxton, which was attributed to syphilis. 1928). Lambert (1931) concludes that this was so for Venereal syphilis alone occurs in the Americas Renell and Bellona Islands in the southern Solomons. north and south of the two tropics but would, of There are strong suspicions from the journals of course, be primarily a disease of urban populations Captain James Cook and other early explorers of this in them. area that yaws was present in many Pacific is!ands in In Africa an equatorial belt of yaws is bordered the mid eighteenth century. Its presence in New north and south by zones of endemic syphilis in Zealand is uncertain; the Maoris are believed to semi-arid areas, while venereal syphilis predominates have reached New Zealand from Polynesia about along the Mediterranean littoral and in the southern the middle of the fourteenth century and to have part of Africa. The last can be disregarded for the displaced the previous inhabitants. Yaws has, since present purpose as three centuries of migration have 1950, been found endemic in the interior of West confused the picture in the originally scanty popula- New Guinea where European exploration and tion south of the Kalahari. In the Kalahari, endemic administration had not previously extended (Kranen- syphilis was the indigenous treponematosis until the donk, 1958). The presence of yaws (Yu, 1957) in present decade (Murray et al., 1956). Endemic syphi- China (Kiangsu, north of latitude 30°N) is probably lis has also been reported in East Africa (Davies, due to its repeated introduction by Chinese return- 1956). However, the disease in Buganda Province, ing from southern lands where yaws was endemic Uganda, has become more definitely venereal syphi- (Maxwell, 1916). Yaws was also present in the lis during the present century, and this may raise some aborigines in southern Taiwan (Takahashi, 1939). doubts about its true nature (see pages 10 and 29). In Australia the treponematosis pattern probably The populations of the Mediterranean littoral of resembled that in Africa in the same southern lati- Africa have undergone many centuries of migration tudes. Bone lesions and serological reactions indi- and invasion and for all that time have been pre- cate that endemic treponematoses occurred among dominantly of races different from the rest of Africa. aborigines in Central Australia and further south No evidence of venereal syphilis in the early Egyptian (Hackett, 1936a).' While yaws was the infection in remains so far examined (Williams, 1932; Rowling, the tropical northern Australian coastal area, the 1961) has been found, although gonococcal salpin- recently increased knowledge about endemic syphilis gitis has been reported. suggests that possibly the treponematosis, irkintja In Europe, venereal syphilis is universal except for (Hackett, 1936a), in semi-arid central and southern the anomaly of a non-venereally acquired endemic Australia might have been endemic syphilis. Pro- syphilis in parts of Yugoslavia-e.g., Bosnia, where fessor J. B. Cleland of Adelaide (personal com- it has been known for several centuries since the munication, 1962; and Black & Cleland, 1938) has arrival of Ottoman invaders (Grin, 1953; and long proposed that irkintja was a non-venereal page 10). However, in the endemic treponematosis treponematosis other than yaws. The aboriginal of Yugoslavia, occasional cardiovascular and central population and its cultural introductions came into nervous system lesions, although mild, are reported; Australia in several waves from the north and north- this is unusual in endemic syphilis elsewhere, except west (see page 26). The nearest endemic syphilis in Buganda. area lies far to the north-west; thus yaws coming In Asia, endemic syphilis is present in the rural into northern Australia from Asia may have been areas of Syria, Saudi Arabia, Iraq and adjacent Iran and used to occur among the nomadic pastoral 1 MacKay (1938) concludes that the pathological changes in aboriginal bones found near the River Murray in New people of the Central Asian semi-arid steppes. South Wales are most likely due to venereal syphilis. He had In India, yaws is an isolated remnant of a probably excluded endemic syphilis, yaws and " some indigenous disease of which we have no medical knowledge, which also originally widely distributed disease and in Ceylon it produces these striking pathological lesions in bone ". He is traditionally thought to have been introduced or said that at that time there was little evidence that bone lesions occurred in yaws. Cleland (1928) also refers to perhaps reintroduced from Africa following Euro- aboriginal bones with " osteitis and periostitis (possibly pean discovery (Spittel, 1923). From Assam, it syphilitic) ". ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 17

the precursor of endemic syphilis in the semi-arid first step in such a study should be to draw up steppes of central Australia.' diagnostic criteria for the diseases likely to be seen The bone lesions of yaws (Hackett, 1951) and in such bones. Radiographic and microscopical endemic syphilis (Rost, 1942) appear indistinguish- examinations should be made. Descriptions of bone able except that in the latter goundou (Botreau- lesions in endemic syphilis (Rost, 1942) and in yaws Roussel, 1925) does not occur or is extremely rare. (Hackett, 1936a, 1951) should be of value in these However, in yaws endemic areas out of Africa studies, as should be the publication on the bone goundou does not occur or, again, is extremely rare lesions of leprosy by M0ller-Christensen (1961). (Botreau-Roussel, 1961). However, the possibility that some of the leprosy of Dr E. I. Grin of Sarajevo, Yugoslavia, (personal pre-Columbian Europe might have been syphilis communication, 1962) has occasionally seen goun- should be carefully considered. Williams (1932, dou in endemic syphilis in Bosnia, and it has been 1936) has commenced this study and stressed the said not to be rare in Khuzistan (Iran). difficulties of the diagnosis of venereal syphilis in Venereal syphilis on the map (Map 1) may be ancient bones and also the difficulty of dating them. regarded as occupying the areas not previously Williams concludes that there is no certain evidence "committed " to the endemic treponematoses. of venereal syphilis in pre-Columbian bones in From this information the geographical distribu- Egypt or Europe but he accepts some of the osteo- tion of the treponematoses about the beginning of logical evidence of venereal syphilis in American European explorations by sea (sixteenth century) Indians before Columbus's arrival. Holcomb (1940) (Map 2) may be guessed as follows: comments on Williams's (1932) conclusions. How- ever, all this needs reconsideration, especially since Pinta: in Central America and South America, Hrdlicka (1932; Lawrence, 1941) a leading anthropo- mainly in humid hilly or mountainous areas, logist of the Amerindian, has stated that " from absent elsewhere; evidence of thousands of Indian skulls and skeletons Yaws: in the tropical belt, but perhaps less ex- predating the arrival of Columbus, there is, as yet, tensive in India and absent in the Americas; not a single instance of thoroughly authenticated pre-Columbian syphilis ". Endemic syphilis: in semi-arid steppes of northern and southern Africa, central Asia and probably In some pathological museums skulls with lesions central Australia; absent in the Americas; labelled " syphilis " from burials in countries where endemic treponematoses, particularly yaws, have Venereal syphilis: in Europe and the Mediter- occurred have probably been wrongly diagnosed. ranean basin; absent elsewhere. If effective treatment had not been discovered but The introduction of venereal syphilis into Europe present-day improvements in living standards had by Columbus from the Caribbean islands has often nevertheless occurred, endemic syphilis and yaws been debated with more heat than light. The history would probably be receding as they are now doing; of venereal syphilis needs careful review (see page however, chemotherapy has doubtless hastened this 28). Venereal syphilis in the tropics in the eight- recession by a generation or more. The difference in eenth and nineteenth centuries was probably often severity of yaws in Africa and Indo-China com- confused with yaws (Hackett, 1936b). mented upon by Botreau-Roussel (1962) was prob- Reports of examinations of human bones of all ably due to differences in the stage of recession (see periods, especially before 1500, from all parts of page 20). Bancroft (1769) speaks of the very the world, in museums and elsewhere, should be extensive eruptions of yaws in African slaves in reviewed for descriptions of lesions likely to have Guiana. From the time that venereal syphilis in been caused by treponematoses, and bones not so Europe first attracted attention at the end of the reported should be carefully examined. Perhaps the fifteenth century, it has extended into or been recog- nized in most countries in which yaws or endemic I In 1803 the explorer Mathew Flinders met a large fleet syphilis is not present. It is thought to have become of a thousand Malay trepang fishermen on the Arnhem less dermal and destructive and to involve the central Land coast, north Australia; the trepang industry was, even then, long established. The dried and smoked molluscs were nervous and cardiovascular systems more frequently sold to Chinese traders in Timor. The epidemiological now than then. Perhaps in the better-educated com- significance of this trade as regards the treponematoses is unknown, but is probably small. Earlier in the present munities of modern highly developed countries, century this trade was mainly in the hands of Japanese. venereal syphilis would naturally have tended to 18 C. J. HACKETT recede to its basic reservoir in the " submerged Although a number of spirochaetes have been tenth ". observed from lesions in animals of many zoological Animal treponematoses orders no other treponeme closely resembling T. pal- The only treponeme in animals which is micro- lidum has been found. Careful serological search, scopically indistinguishable from the human palli- using treponemal antigen, might reveal other such dum/pertenue treponeme is T. cuniculi. This causes a infections which might be of practical as well as natural venereal infection in rabbits. The organism theoretical interest. was found by Bayon in 1913 and has not yet been cultivated. The rabbit is a European animal but THE CAUSAL ORGANISMS this treponematosis may have arisen in Europe or elsewhere. The pauidum/pertenue treponemes McLeod & Turner (1946) have reviewed the litera- These microscopically identical treponemes are ture on this infection and described the clinical thin spiral organisms about 6-15,jz in length and about manifestations following intracutaneous and intra- 0.25, thick. The spirals are remarkably uniform and testicular inoculation. Natural infections start with measure about l,u x 1It. Their microscopical ap- a genital initial lesion after an incubation period of pearance and movements as seen under darkground two to eight weeks. Metastatic skin lesions have fol- illumination are characteristic. lowed intratesticular inoculation when there was no The treponemes of the pallidum/pertenue group possibility for auto-inoculation, which shows that comprise three named species: infection of the blood-stream must have occurred. Treponema pallidum, Schaudinn (1905): venereal These lesions differ from those of T. pallidum lesions syphilis and endemic syphilis; 1 in rabbits. Skin lesions start as erythematous papules Treponema pertenue, Castellani (1905): yaws; which enlarge and become hypertrophic and crusted. Treponema carateum, Brumpt (1939): pinta. Lymph-glands are also enlarged and treponemes can be demonstrated in them by animal inoculation. None has been cultivated in artificial media; thus There are no lesions of bones or viscera. Festenstein the knowledge of their characters and relationship & Bokkenheuser (1961) could not produce con- to each other is incomplete. Further electron- genital infection. They thought the high body- microscopic studies of the morphology of these temperature (39°C) of rabbits was unfavourable for treponemes are needed (Swain, 1955), but important the survival of the treponeme (see page 27), but differences between them are unlikely to be found the part possibly played by placental structure may (Molbert, 1956). need to be taken into account. Experimental animal infections have shown fairly Turner & Hollander (1957) found considerable consistent differences in the lesions caused by the cross-protection between T. cuniculi, T. pallidum and treponemes of yaws, endemic syphilis and venereal T. pertenue, but the cross-protection between the syphilis (Turner & Hollander, 1957). The greatest last two was stronger than that between T. cuniculi differences were between lesions caused by the and either of the others. Because of this close im- treponemes of yaws and venereal syphilis, while munological relationship with the others, T. cuniculi those of the treponemes of endemic syphilis were may be a nearer descendant of the unknown fore- usually intermediate. However, the differences runner in animals of the human pathogenic trepo- observed in one animal-i.e., rabbits-did not always nemes (see page 24). The sera of infected rabbits agree with those found in another-i.e., hamsters. become reactive to the reagin and treponemal tests. Workers in this field have stressed the unavoidable The pathological changes consist of infiltration by lack of precision and the relatively small numbers lymphocytes and plasma cells much as in yaws and and small range of observations that have been made. venereal syphilis. Perivascular infiltration is slight. Rabbits may not be very suitable animals for ex- Latency is frequent. The infection may last from perimental work because of their higher body- several months to more than a year and cause death. temperature (390C) (Festenstein & Bokkenheuser, Infection rates in some stocks of rabbits may be 1961). nearly 40%. Man, apes and monkeys are reported to be insusceptible and inoculation of white mice 1 Ifthe treponeme ofendemic syphilis is later differentiated and rats, guinea-pigs and hamsters gives rise to a from that of venereal syphilis, it might be named T. trepe- latent infection (McLeod & Turner, 1946). narida. ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 19

In man yaws or syphilis of more than one year's Little help in the differentiation of the treponemes duration probably renders the patient non-sus- is to be had from the response of their infections to ceptible to superinfection with the same treponeme chemotherapy. All treponemes are about equally or infection with the other (Medina, 1954, 1959). susceptible to penicillin (Turner & Hollander, 1957). However, the studies of Guimaraes (1946) and the A single dose of 1.2 mega-units causes disappearance statements of Edmundson et al. (1953) 1 do not fully of the treponemes within 24 hours and is followed agree with this. Medina (1954) found that a few by rapid healing of early lesions. untreated pinta patients in the early or late stages Small dosage is in general use in mass treatment could not be infected with virulent yaws treponemes. campaigns against the endemic treponematoses-a In the absence of attempts to infect pinta patients single dose of 1.2 mega-units of procaine penicillin with syphilis treponemes, however, one might expect (Hackett & Guthe, 1956). This rapidly makes the pinta patients to be resistant to syphilis. This would patient non-infectious and probably prevents in- not favour the presence of venereal syphilis in the fectious relapses for some years. These are com- Amerindians when Columbus arrived. However, munity measures and although some early infections Medina refers to studies by Blanc in which patients may be cured, as judged by sero-reversal, others and in various stages of syphilis could be readily infected late infections cannot be expected to be serologically with the treponeme of pinta " as if there were no cured but clinical relapses will be infrequent. The immunity of any kind". intention in mass campaigns is to stop the trans- The experimental work in animals of Turner & mission of the disease in the community and the Hollander (1957) showed that with adequate dura- small dosage is justified by its effectiveness and tion of infection there was complete cross-protection reasonable cost and by the absence in yaws of between different strains of venereal syphilis and severe late manifestations of the brain and heart. endemic syphilis treponemes and between different In venereal. syphilis, treatment is of patients and strains of yaws treponemes; there was less between with larger doses in longer courses-4.8 mega- treponemes of venereal syphilis and those of yaws units during one to two weeks in early venereal and least between those of venereal syphilis or yaws syphilis-because of the severe late lesions of this and T. cuniculi. This indicates the close relation- disease. Even in syphilis a number of early infections ship between the three human treponemes (see page may be cured by the small doses used in mass cam- 24). Smaller differences in cross-protection have, paigns against yaws but this would not justify their however, been demonstrated between the treponemes use in venereal syphilis. from different syphilis patients (Turner & Hollander, A better understanding of the relationship of the 1957). Turner & Hollander (1957) conclude that on treponemes to each other should follow the study of the basis of limited evidence there is a fundamental their antigenic characters when their cultivation is difference between the various types of treponemes possible. Strains of T. pallidum that can at present (excluding that of pinta). They also state that with be cultivated are regarded as non-pathogenic variants rapid passage in rabbits there is a tendency for the and in them other differences from the pathogenic selection from populations of yaws treponemes of treponemes from man have been found. those with characters of the syphilis treponeme. Site of entry and transmission of the treponemes It should be recalled that the treponemal antigens Three of the treponematoses have initial lesions at are components of the structure of the treponemes the site of entry of the infection. This is characteristi- themselves and as such are genetically determined. cally in venereal syphilis on the genitalia and in Serological findings reveal no differences between yaws on the skin elsewhere than the genitalia, most the human treponemes and may be summarized as frequently on the leg below the knee. In pinta the follows: initial lesion, although not frequently seen, may 1. Sera from venereal syphilis, endemic syphilis, occur on any exposed part of the skin. The number yaws and pinta react to the same antigens. of treponemes capable of transmitting infection may 2. Serological cross-reactions with present tre- be small (see page 11); however, many treponemes ponemal antigens occur with sera from venereal may be expected to be inoculated in the natural syphilis, yaws and T. cuniculi infections. transmission of yaws and of venereal syphilis and few in pinta and endemic syphilis. The larger num- 'Edmundson et al. (1953) state that in some rural com- bers be to favour the transmission munities in Mexico in which pinta is " highly endemic ", might expected syphilis is " considered relatively common". of mutants more than the smaller numbers would. 20 C. J. HACKETT

In venereal syphilis transmission is most often by occasional implantation in the axilla or elsewhere treponemes from genital condylomata or initial which produces a condyloma or dry annular lesion. lesions; a few infections may come from buccal or In endemic syphilis Guthe & Luger (1957) suggest anal mucous papules but these are not usual. The that, as in yaws, fingers might play an important predominance of sexual contact in the transmission part in transmission. Grin (1953) considers that the of venereal syphilis is probably also related to the transmission of endemic syphilis in Yugoslavia was fact that sexual contact is one of the closest direct related to the indiscriminate use of drinking utensils physical contacts among adults. and unhygienic village conditions. Perhaps the most In yaws infectious lesions are predominantly the important factor is defective personal hygiene in papillomata of the early stages that may occur any- childhood. where on the skin; early mucous papules and the In pinta the initial lesions are often not recognized, relatively non-infectious palmar and plantar hyper- but they resemble the early ones. The source of keratoses and late lesions are probably not impor- infection must be the dry papular or pigmented tant sources of infection. The frequency of initial lesions from which treponeme-containing serum can yaws lesions on the lower part of the leg may be be expressed. The difficulty in understanding how explained by the treponemes being passed from the treponemes get from these lesions to the skin of a fingers of a patient with moist papillomata to the susceptible person by contact has led to the sugges- fingers of a susceptible person, who, upon rubbing tion that a biting insect, such as Simulium, might his leg in response to the irritation of a minor injury, play a part (Sanchez et al., 1961). However, no close implants the treponemes on a small abrasion geographical association has been reported between (Hackett, 1957b).' Yasuyama (1928) found that pinta and onchocerciasis, which is transmitted by T. pertenue in serum remained infectious at 28°C for certain species of Simulium, but pinta may be trans- up to two hours. mitted mechanically by other species. Powell (1923) in Assam, in what he says was a Again, it must be stressed that pinta, yaws and closely supervised population on tea plantations, endemic syphilis are characteristically transmitted failed to observe initial lesions in 20 % of 205 patients among children by non-venereal contact and that who developed generalized early yaws 25-121 days venereal syphilis is transmitted among adults through after the presumed infection. The others developed sexual contact. lesions identical with the characteristic papillomata, In yaws, infectious lesions may be large, perhaps except perhaps for being larger, 17-63 days after the many square centimetres, and very infectious; in presumed infection. This was a prospective study. pinta they may be even larger but less infectious; No other similar data are known but initial lesions and in endemic syphilis and venereal syphilis the are probably at least as frequent as Powell reported. area may be less, one or two square centimetres, and In endemic syphilis initial lesions are so unusual again very infectious. Infectious lesions may remain that, for practical purposes, they are often regarded in yaws, endemic syphilis and venereal syphilis for as not occurring. The source ofinfecting treponemes several months and recur during three to five years; in endemic syphilis is usually thought to be the in pinta they may persist for many years (see Table 1 buccal mucosal papules and less importantly the less above). frequent condylomata. Where the treponemes enter Spreading circinate lesions may occur in endemic the body is not known. Either the entry occurs syphilis and less frequently as a variation of papillo- without any cellular reaction or, what is more prob- mata in the later part of the early stage of yaws. able, the cellular response resembles the earliest In the recession of yaws (Hackett, 1959) transmis- recognizable lesion. In endemic syphilis, this might sion and severity of clinical manifestation are de- be the solitary papule on the buccal mucosa, especi- creased, that is, as found at surveys early lesions are ally if unilateral lymphadenitis were also present less numerous and drier and late destructive lesions (Luger, 1958). Perhaps such small solitary papules are less frequent and less severe or absent. In the are, in fact, initial lesions and, following later blood- later stages of yaws eradication, isolated new borne dissemination, only those treponemes reaching cases occur which may be accounted for either by the buccal mucosa cause lesions, except for an unusually prolonged latency or, as Dr F. N. Guima- raes of Rio de Janeiro (personal communication, 1 The role of flies in the transmission of yaws, although 1952) has found, by unexpected infectiousness of possible, is probably not important. It has been discussed by Barnard (1952). solitary hyperkeratosis of the palms and soles or of ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 21 late destructive lesions. Such possibilities are not At present, endemic syphilis and venereal syphilis readily apparent when the disease is rampant. are not the same disease and their treponemes, The essential factors that cause spontaneous reces- though closely related, do not appear identical. sion cannot at present be more precisely defined than as "improved standards of living ". More Other treponemes in man and nature complete knowledge about these might well be of A number of treponemes have been reported from value in the problem of the origin of the treponema- man, such as T. macrodentium and T. microdentium toses as well as in the prevention of yaws. However, in the mouth, T. calligyrum in smegma and T. euygu- soap, through its direct effect on personal cleanliness, rata in the intestine, but none is morphologically may aid the recession of yaws by reducing trans- identical with T. pallidum, and none would be mission. This would be related to the time taken for expected to have been its forerunner. the treponeme to enter the body and its survival time Veldkamp (1960) and de Bruijn (1961) report on the surface of the skin. On the other hand, soap " studies on a small, anaerobic, free-living organism may merely be an indicator of prosperity and im- whose morphological characters are intermediate proved standards of living ". between those of Borellia and Treponema. However, After the treatment of all patients who have " PAM 1 it was found to have the group-specific protein active yaws with an adequate single dose of antigen " of T. pallidum (Reiter). Veldkamp (1960) and the administration of single half-doses to the it T. zuelzerae. remainder of the population (total mass treatment; named Hackett & Guthe, 1956), infectious lesions rapidly The present knowledge of the treponemes in ani- disappear and infectious relapses from early latency mals and of saprophytic treponemes in the tropics are mostly suppressed for some years. The re- is inadequate. establishment of infectious yaws after total mass treatment is slow and probably arises from the in- EVOLUTION OF THE TREPONEMATOSES frequent infectious relapses or from infectious cases entering the population (Hackett, 1960). There may Origin ofhuman infections well be little effective transmission in a yaws endemic During the more than half a million years of man's community with high serological reactor prevalence existence most human infectious diseases, except (60 %-80 %). Harding (1949) in Sierra Leone de- those due to viruses, have probably arisen from: monstrated the high proportion of infectious yaws patients in such conditions that are relapses and the (a) free-living or saprophytic organisms, importance of relapses in transmission. (b) commensals or infections of insects, In the present low-prevalence phase of venereal syphilis recession in certain countries, the spread of (c) infections of warm-blooded animals. syphilis in a series of small " epidemics " arising Some human infections are comparable to, if not from individuals has clearly shown the epidemio- identical with, certain existing animal infections. logical importance of the social activities of the These range from malaria, various helminthiases individual (Hartmann, 1956; Olansky & Price, 1956). and tuberculosis, to the animal infections that give This also indicates the section of a community which rise to human infections, such as brucellosis, orni- is the infectious reservoir of syphilis and towards thosis, plague, rabies, Q fever and leptospirosis, in which public health measures should be directed. which man-to-man transmission is infrequent or Dr E. I. Grin (personal communication, 1962) absent. found in Yugoslavia during the 1939-45 war that In human infections for which no animal source is endemic syphilis extended beyond its usual geo- known, the original animal infection may have died graphical area. However, after 1945, with the general out or may not have been discovered. However, improvement of living conditions and the successful such a human infection may have originated much mass treatment campaign, the disease rapidly de- later as a completely human possession from a creased. By 1960 endemic syphilis had been eradi- saprophyte or commensal (Burnet, 1962). cated in Bosnia. No animal reservoir of the human treponemes is known although T. cuniculi infection in rabbits may as a common ancestor 1 Procaine penicillin G in oil with 2 % aluminium mono- be regarded possibly having stearate. with them (see pages 18 and 24). 22 C. J. HACKETT

Infectious contacts in man be effective because of the number of infective The transmission by contact of a communicable organisms involved and because of their invasive- disease from an infectious to a susceptible person will ness and may have become necessary because of be more likely the closer the physical contact and their lack of survival away from the body and the the less the personal cleanliness. Transmission by anatomically restricted sites of effective infective hand-to-hand contact is clearly shown by the trans- lesions. However, not all sexual contacts with a mission of bacillary dysentery and poliomyelitis patient with infectious syphilis result in transmission, where other opportunities are limited. but the proportion is not known. The transmission Only adolescents and adults are likely to have the of venereal syphilis in adults would probably cease necessary genital contacts for venereal transmission. without sexual contact; it would not be expected to However, transmission by indirect contact, through " revert " completely to some simpler contact trans- towels, occurs in gonococcal ophthalmia and vulvo- mission without deterioration of personal hygiene of vaginitis, and non-venereal transmission of venereal the population. This stresses the closeness and per- syphilis to children can occur in unhygienic and haps transience of the infecting contact between crowded conditions (Eisenberg et al., 1949; Taylor, children which is adequate for the transmission of 1954). endemic syphilis and yaws, because the treponemes Contact between children and adults, except be- of those infections are just as unable to survive away tween children and parents, is usually less frequent from the body as that of venereal syphilis. The types and less close than among children themselves. and closeness of skin contacts between children in Probably contact between adults, except between rural endemic treponematoses areas should be care- marital partners, is the least close. This is also sup- fully considered, in addition to the question of ported by findings in leprosy (Bechelli, 1954). Sosa- handling by older members of the family. They may Martinez & Peralta (1961) report transmission of be guessed at from the contacts among urban pinta between husband and wife as well as from children. parents to children, although other observers have Among the various devices which ensure the not found this frequent. transmission and thus the survival of communicable The importance of any particular contact in the diseases closeness of contact, long periods of in- transmission of a communicable disease depends fectiousness and latency with infectious relapses are upon the ease or certainty of the passage of perhaps important in the treponematoses. a single organism from an infectious patient to the Size of community needed to maintain infections susceptible person. Enormous numbers of organisms Each communicable disease needs a community may be shed by an infectious patient but probably of a certain size, otherwise it cannot maintain itself. only a few (see page 11) are, of necessity, sufficient A highly infectious disease of short duration with to infect a susceptible person. However, larger in- high mortality which produces lasting immunity in ocula may favour the transmission of mutants (see survivors would require a large population and the page 19). arrival, by birth, of many susceptibles. However, a In a community where adults are generally communicable disease of lesser infectivity but of clothed, genital contact in coitus might have become longer duration of infectiousness or having infectious the method of transmission in venereal disease be- relapses from latency during a number of years cause, although as an infectious contact it is relatively could maintain itself in a smaller population. transient, it is as direct and as close as any contact The treponematoses other than pinta have a among adults. potentially infectious period of between three and Because the gonococcus flourishes mainly in the five years. This is not long enough to allow the genito-urinary tract, apart from the occasional transmission of endemic treponematosis from transmission by hands, flies (ophthalmia) or inter- parents to children in a family but it is long enough mediate inanimate objects, its transmission must be in sufficiently large populations to ensure the trans- largely restricted to sexual contact. mission of infection from a relatively few infectious In venereal syphilis, treponemes abound in the patients (4%; Hackett, 1960) to the uninfected initial (genital) lesions, in condylomata (mainly susceptibles (40%) and its continuity in the com- genital) and buccal mucosal and early skin lesions- munity. yet transmission is predominantly by genital contact. Endemic treponematosis in Australia was able to Such a transient and rather restricted contact may maintain itself in nomadic aboriginal family groups ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 23 which congregated into larger groups for only a few fatal consequences when such people are suddenly weeks each year, although there were probably a settled. Under natural conditions such a tremendous few other opportunities for limited contacts with change would be very gradual with the consequent occasional solitary visitors or visiting families. adaptation of their infections to the people. Since venereal syphilis is transmitted almost Burnet (1960) has pointed out that the persistence entirely among adults, it will need a larger and of herpes virus suggests that in such primitive con- denser total population than the endemic treponema- ditions it would be an asset for an infection to toses. This doubtless influences its urban distribu- remain infectious long enough for parents to infect tion. their own children. Because treponemes can be ob- On the other hand, with its larger area of skin tained from pinta skin lesions of the same patient involvement but similar duration of infectiousness for long periods, pinta may be one of these early (three to five years), yaws could be transmitted from diseases (see also Sosa-Martinez & Peralta, 1961). child to child in large family groups such as occur Only when man came to live in larger groups and with polygamy. This may have occurred in the thus to be, at least in part, more sedentary could nomadic, food-gathering aborigines of Northern communicable diseases of shorter infectious periods Australia. However, children of sedentary popula- have arisen. tions are usually infected with yaws by children from To summarize, the first human infections to be- outside their family. come established probably had long infectious The earliest human beings probably passed most periods. Only in sedentary and especially in urban of their time in family groups, the size of which populations would those with short infectious depended upon the available food and water. These periods evolve. However, the endemic treponema- primitive human population groups, living as dis- toses have maintained themselves among nomadic persed, nomadic food-gatherers, probably had speci- food-gatherers of the present century. fic group territories with water points, hunting grounds, vegetable food and firewood sources and ORIGIN OF THE HUMAN TREPONEMATOSES perhaps extraterritorial salt sources. The family groups ranged over their own tribal areas, occasion- The probable distribution of the treponematoses ally meeting other families of their own tribe, more at the beginning of the present century may be used rarely members of other tribes. Annually, or more as a starting-point for a discussion of their origin. or less frequently depending on the availability of The distribution in Map 1 is, within broad limits, food and water and upon the need, family groups probably moderately accurate.' It is based upon gathered for communal purposes lasting a few days reports from about 1900 with the omission of state- to a few weeks. These gatherings increased the ments that can now be reasonably regarded as effective size of the population, even if only for a errors of diagnosis or interpretation. Until the few days, and would greatly assist the spread of present century " disgusting " or " revolting " disease communicable diseases. manifestations were often reported as syphilis by The size of the group that can live as nomadic explorers and even by doctors (Hackett, 1936b). The food-gatherers depends upon food supplies: the Treponema pallidum of venereal syphilis was then group might be large in fertile areas but would be unknown, and diagnosis depended upon clinical small in savanna and even limited to a family in examination. That yaws was not well known is clear semi-arid steppes. Tindale (1960) estimates that the from descriptions of the time (Charlouis, 1897; average tribal group in central Australia was fairly Manson, 1898) and also by the fact that the late constantly about 500 and that the area of its tribal destructive changes were not generally accepted until territory ranged from 50 to 3-5 or less square miles the 1920s (van Nitsen, 1944), despite the able de- per person, depending upon the ability of the country scriptions by Rat (1891) and others of the " tertiary to support the hunting and food-gathering way oflife. period " in yaws. Although Moseley (1800) said that Increase in size of a group is possible only when the yaws " ends in shocking nodes and destruction of the food supply throughout the year is assured by the bones ", Nicholls (1899) thought that " the sequels domestication of food plants and animals. Cook of yaws " and " the tertiary symptoms " resulted from (1949), writing about the Australian aborigines, has treatment with mercury. There was much confusion pointed out that the sanitary habits that might be adequate for nomadic family groups can lead to I See footnote on page 15. 24 C. J. HACKETT between yaws and venereal syphilis in tropical coun- However, such an alternative independent origin of tries. Endemic syphilis as seen in arid lands was not pinta would not change the main proposals in this clearly recognized until the third decade of this cen- paper. tury (Lacapere, 1923). Pinta was regarded as a Professor Adler has also stressed how minute mycosis until after 1930 and many were the " causa- biological differences in morphologically identical tive " fungi described from it. treponemes may cause major epidemiological dif- The geographical distribution of the treponema- ferences, as is also seen in Leishmania and Borellia. toses in Columbus's day would be of great assist- Although no thorough search has been made, no ance in considering their origin and Map 2 is an natural animal infection with a treponeme resembling attempt to provide this (see page 17). those of the syphilis/yaws group is known except The mixture of ignorance and error, and some- that with T. cuniculi in rabbits. This is a disease of a times even emotion, in writings and discussions of European animal (see page 18), but, because of the the origin of the treponematoses, may be due in resemblance of its treponeme to those of the human part to the fact that few workers have had adequate treponematoses, it would appear to be related to personal experience of all of them. some forerunner of the human infections which In putting together the rather inadequate evidence probably started in a part of the world with a warmer on the origin of the treponematoses, account should climate than Europe ever had. This would strongly be taken of the behaviour of other infections both in suggest that the human pathogenic treponemes arose the field and in the laboratory. The temptation more directly from an ancient animal infection than should be avoided to deal with " awkward cases" from a saprophyte or commensal. by making exceptions or special situations. The curative effect of an induced attack of malaria An initial problem is the interrelations of the in late syphilitic lesions of the central nervous system treponemes themselves. The close relation of the has been demonstrated in the present century. Thus treponemes of yaws, endemic syphilis and venereal the influence of highly endemic malaria on the course syphilis is obvious and the intermediate position of of venereal syphilis and of other treponematoses in endemic syphilis to the others is stressed by Turner & tropical countries needs review and further careful Hollander (1957). The treponeme of pinta, although study, although relatively little high fever may be microscopically identical with the other treponemes, experienced by adults under these conditions. This has never been transmitted to animals, although such study, however, may not be possible until more is transmission is relatively easy with the other trepo- known of the role of auto-immune phenomena in nemes. Moreover, pinta remains infectious for many the clinical manifestations of the treponematoses. years, which is quite uncharacteristic of the other treponematoses. Step I-Pinta (Map 3) Professor S. Adler of Jerusalem (personal com- As already mentioned, pinta has many charac- munication, 1962) has called attention to the need to teristics of a primitive infection, such as lack of define more precisely the relationship of the trepo- invasion of deeper tissues than the skin and a long neme of pinta to those of the other human trepone- duration of infectiousness which would maintain it matoses. The closer this relationship, the more in small population groups, even in families. These likely it is that the four human treponemes are a suggest that it is an early human treponematosis. consecutive series starting with that of pinta (see Another characteristic that must be taken into hypothesis A in the accompanying diagram). The account in considering its origin is its present isola- less close this relationship, the more likely it is that tion in the Amerindian populations in humid areas the treponeme of pinta is an earlier and independent of the Americas (Map 1). branch from the treponeme of an ancestral animal The proposed original treponematosis, pinta, infection (see hypothesis B in the diagram). He might have extended throughout Africa and Asia favours the latter possibility. However, in this paper and into the Americas with the migration of man the former has been proposed because of the occur- and other animals over the ice-free Bering Strait land rence of somewhat similar depigmentation in pinta bridge which probably last existed about 15 000 to and in the other treponematoses. For this reason an 10 000 B.C. (Zeuner, 1958). This would have been independent origin for pinta in the Americas and during the last part of the last (Wisconsin) glaciation another for the other human treponematoses in the before the ocean levels had risen from the melting Euro-Afro-Asian land mass has not been proposed. of the polar ice-caps (Haag, 1962). Willett (1953) ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 25

TWO HYPOTHESES AS TO THE POSSIBLE EVOLUTION OF THE SYPHILIS- YAWS TREPONEMES

HYPOTHESIS A HYPOTHESIS B WHO 3142

says that the end of this glaciation "is usually or more thousands of years before man's first entry placed at approximately 6500 B.C.", but it is now into Australia. Except for the dingo, which probably more generally regarded as being about 8000 B.C. accompanied man in his boat, and rats and bats, It can be confidently assumed that little came out the indigenous mammals of Australia and Tasmania of the Americas after the last glaciation until were all marsupials or monotremes of more ancient Columbus's discovery in the late fifteenth century. ancestry; thus Australia, from a zoological point of Had pinta-like the primitive marsupials now view, must have been isolated from the Euro-Afro- isolated in the Americas and Australia (Mathew, Asian land mass much earlier than were the 1939)-been world-wide, one would expect to find Americas. pockets of it in isolated and especially peripheral Pinta might have been expected to have survived, communities such as the Australian aborigines (see had it ever been present, among isolated communities also Darlington, 1957). An Indonesian corridor to such as the pygmies and negritos in remote mountain Australia would have had water crossings of 20 miles fastnesses, but no report of this is known. 26 C. J. HACKETT

Although all the pigmentary changes characteristic a humid, warm environment favoured mutants of of pinta are not seen in yaws areas, loss of pigment the pinta treponemes which were more invasive and frequently occurs in many such areas on the hands destructive of tissue and which caused yaws. This and wrists which closely resembles some of the might have occurred about 10 000 B.C. Yaws then changes reported in pinta and has sometimes caused spread through the Afro-Asian area, but did not confusion (see page 15). Some of these pigmentary reach the Bering Strait before it was again flooded. losses are associated with the plantar hyperkeratosis The last glaciation was extensive and many of the of the later stages of yaws (Hackett, 1957a, 1960). now arid geographical areas probably enjoyed good Other pigmentary losses occurring in yaws areas do rainfall and a more uniformly warm climate. Thus not appear to be due to a treponematosis and do yaws might have appeared anywhere in Africa and not respond to arsenical or penicillin therapy. southern Asia where the environment was favourable In attempting to date the spread of an infection and spread widely to reach Australia and the Pacific from the Euro-Afro-Asian land mass to the peri- islands if or when they were inhabited, but not pheral Americas and Australia it had been thought America. that the absence of genes for the blood groups A Of mutation among the treponemes little is and B from the Indians of South America and of that known and little may be learnt before they can be for B from the Australian aborigines (Mourant, cultivated. Because drug resistance has not yet 1958) would be useful. Recently, however, these developed in treponemes, mutation affecting other blood groups have been found in certain apes, thus characters is not excluded. The treponemes would their dating value has diminished. be expected to undergo mutation at a rate compara- After taking the above points into consideration, ble to that found in other micro-organisms, but only it is here proposed that pinta arose from an animal those mutants would survive which changing clima- infection in the Euro-Afro-Asian land mass, perhaps tic, social or other conditions favoured. before about 20 000 B.C. and had spread through Only T. pallidum of venereal syphilis flourishes the then accessible world by about 15 000- B.C. in a wide range of climates; the others appear rather (Map 3). strictly limited to warm climates either humid This leaves unexplained the lack of evidence of (yaws and pinta) or arid (endemic syphilis). survival of mutants of pinta treponemes in the Mr N. B. Tindale of the Department of Anthro- Americas as it is proposed below happened else- pology, South Australian Museum, Adelaide where. If the differences of colours of the pinta (personal communication, 1962) says that man was lesions reported from different South American almost certainly in Australia for part of the last countries are real, these may be due to mutants; half of the last glaciation, perhaps before 20 000 B.C. perhaps the environment may have been too constant and that three separate racial groups came into to favour mutants. The Americas differ from the Australia from Asia. The earliest known were other continents in that desert zones are much less negritos, who were short in stature, dark-skinned extensive because both North and South America with crisp, curly hair and of a different race from are so narrow in the latitudes concerned. A study later arrivals who displaced them. Their most of yaws in Africa in environments resembling those obvious survivors were the Tasmanians (Tindale, in which pinta is endemic might be instructive. 1960). No pathological changes suggesting trepone- Step 2- Yaws (Map 4) matoses have been described in the few Tasmanian Pinta is assumed to have spread originally through- bones that have survived. out the world by about 15 000 B.C. and to have been The extension of yaws across the Bering Strait cut off in the Americas from the main land masses would have been checked by the rising of the sea after about this time. Maps 1 and 2 indicate the levels due to the melting of the glacial polar caps more recent patterns of yaws, endemic syphilis and about 15 000 B.C., although Lamb (1963) states that venereal syphilis. present sea levels were probably not reached until With the exception of the small areas of endemic later-about 4000 B.C. syphilis in southern Africa and possibly in central In the Pacific islands yaws was apparently present Australia, the most peripheral infection of the three when the first Europeans arrived. Stewart & Spoehr remaining infections is yaws. This may mean (1952), by radiocarbon dating, placed some skulls (Mathew, 1939) that it was the first of the three to from the Mariana Islands with lesions probably due develop. It is therefore proposed that in Afro-Asia to treponematoses at the mid ninth century A.D. ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 27

There is also considerable evidence of yaws in Hawaii The small area of endemic syphilis in East Africa (Samwell, 1786), although mistaken for " the venereal (Map 1) in the Buganda Province of Uganda disease ", and also in Australia (Hackett, 1936b) (Davies, 1956) may have been venereal syphilis with before the arrival of Europeans (see page 16). non-venereally acquired sporadic transmission, In India, yaws has survived in Orissa, Madhya rather than endemic syphilis (see page 29), and this Pradesh and Hyderabad in rather isolated aboriginal may have arrived there much more recently. tribes in inaccessible localities. Reference has already been made (see page 12) Kynsey (1881) and Spittel (1923) state that yaws to the effects of climate on the skin lesions of yaws was introduced into Ceylon, where it was known as as reported by Lopez-Rizal & Sellards (1926), by parangi, meaning " the foreign disease ", by slaves Ramsay (1927) and also by Fitzgerald & Dey (1931). brought by the Portuguese from Africa. Such a One of these was the frequency of buccal mucosal means of introduction may also explain the focus papules in cooler climates; such mucosal lesions are of S. haematobium bilharziasis in Gimvi near characteristic of endemic syphilis. In arid, intra- Bombay. continental climates, the summers are hot and the In Africa, yaws has so flourished that some winters cold but on the average the climate is warm. observers have thought that it was the cradle of the Turner & Hollander (1957) have shown that main- disease. The prevalence and severity of yaws in taining rabbits inoculated with treponemes at cool tropical Africa during the first 30 years of this air temperatures resulted in higher infection rates, century were probably much greater than anywhere shorter incubation periods and more severe lesions else (Botreau-Roussel, 1962). More than one than did maintaining them at higher air tempera- observer regarded yaws then as a bigger burden to tures. The optimal temperature for treponemes is some African populations than all other infections about 35°-37°C and the body temperature of the put together (van Nitsen, 1944). rabbit is about 39°C; above 40°C treponemes are Thus yaws had the capacity in suitable conditions destroyed. Turner & Hollander spezulate about the to become a widely spread, non-killing disease effects of "environmental temperature on the affecting most of the population by adult life. treponematoses in human beings ". To summarize, somewhere in Afro-Asia by about Some observers have reported a higher prevalence 10 000 B.C. conditions favoured certain mutants of of yaws in the cooler rainy season than in the hot dry the pinta treponeme that gave rise to yaws which season (Harding, 1949). However, the temperatures then spread throughout the world except the Ameri- at the cool season in tropical climates would be cas, which were by then isolated by the reappearance much higher than those of the cool season in semi- of the Bering Strait. arid, intra-continental ones, which at night may fall Step 3-Endemic syphillis (Map 5) belowO0C. Fitzgerald&Dey(1931), however, reported On Map 2 an uninterrupted block of endemic thescarcity ofpapillomata in Assam during thewinter. syphilis extends from Africa through western into Marshall (1959) found that resistance of rabbits central Asia, comprising deserts and semi-deserts, to invasion by myxomatosis virus of only moderate often with nomadic populations. There were two virulence was increased at higher temperatures and smaller but perhaps epidemiologically no less reduced at lower ones, and Lwoff (1959) found that important areas of endemic syphillis in similar but higher temperatures checked the development of southern latitudes, in Bechuanaland until recently poliovirus of low virulence. Raised temperatures (Murray et al., 1956) and perhaps in central Aus- did not influence the course of virulent virus strains. tralia in the past (Hackett, 1936a, 1936b). How Turner & Hollander (1957) alsoreportchangesin be- endemic syphilis could have occurred in Bechuana- haviour in experimental animals of a few strains ofthe land is difficult to understand if it did not evolve yaws treponeme towards that of venereal syphilis, es- from yaws. Since endemic syphilis is at present pecially when they were kept under favourable cool air mostly restricted to arid, warm climates these may be conditions (18°-21 °C). Further such studies areneeded. assumed to favour the selection of mutants that gave It is proposed here that mutants of the yaws rise to it. Such conditions would have developed treponeme were selected by arid, warm climates in the present geographical distribution of endemic resulting from the retreat of the last glaciation and syphilis following the end of the last glaciation about that by about 7000 B.C. yaws in such areas had 8000 B.C. and have been maintained, with some changed into endemic syphilis, while in humid warm variations, ever since. climates yaws has continued unchanged. 28 C. J. HACKETT

Step 4-Venereal syphilis (Maps 6 and 7) after the identification of syphilis in the sixteenth In Map 2, venereal syphilis is shown as occurring century and its naming by Fracastorius in 1530. They in Europe and the Mediterranean countries. Of the also refer to writings and edicts (Sudhoff, 1925) relat- origin of venereal syphilis in Europe as in Persia ing to the avoidance of venereal diseases of wider (Elgood, 1951), India (Reddy, 1936), China (Wong, clinical range than gonorrhoea, either before the 1918; Eckstein, 1928) and Japan, there are two main return of Columbus or within the following decades. explanations. Harrison (1959), after careful study, has called atten- One is that venereal syphilis appeared within about tion to the misdating of the earliest Paris edict relat- ten years before or after the year A.D. 1500. Thus ing to grosse verole (Holcomb, 1934) as 25 March Bloch (1908), Hutchinson (1908), Capper (1925), 1493, whereas the correct date is 6 March 1497. Power (1934), Hamlyn (1939) and Harrison (1959) Singer & Underwood (1962) however, suggest that attribute venereal syphilis in Europe to its introduc- perhaps a new strain of T. pallidum was brought to tion by the crews of Columbus's ships returning in Europe from America, which changed the character 1493 from the discovery of America; they cite the of syphilis completely during the closing years of the writings of the sixteenth century to support their fifteenth century. contention. Their main points are the absence of Lancereaux (1868) believed that most of the references in writings before the end of the fifteenth manifestations now known as syphilis were known century to a disease like venereal syphilis as known in Europe long before the Naples " epidemic ". Only at present, statements that it was then a new disease, after that outbreak were many lesions of the various the absence from Europe of pre-Columbian bones stages of the disease related to each other to give the with lesions resembling those of venereal syphilis picture of venereally transmitted syphilis. Previously and the alleged presence of such bones in America. some had been separately described and others were However, diagnosis in some references to " pre- confused with other diseases. Columbian syphilis in America " such as " most Hirsch (1885) stated that there was little doubt likely due to syphilis ", " almost certain evidence of that venereal syphilis occurred in antiquity in Greece luetic infection ", " changes regarded as patho- and Rome and in the Middle Ages in Europe. He gnomonic of syphilis " and " changes consistent also stated that syphilis occurred before the end of with, although not diagnostic of, syphilis" (Cole et the fifteenth century in other parts of the world such al., 1955) leave much to be desired. as India, China and Japan, but that it was taken to References by early writers, in the other countries America and the Pacific islands by Europeans. mentioned above, to syphilis have been thought to European contact with Japan, however, was very have been mistaken; venereal syphilis in these restricted until about a century ago. countries was believed to have been recent and to Cole et al. (1955) state: " Syphilis is a disease of have appeared about the time of its supposed intro- antiquity. It was undoubtedly present from the duction into Europe by Columbus's crews. Venereal earliest times among the Arabians, Greeks, and syphilis was often known by such names as phirangi Romans in the Dark Ages, and it probably came roja (India), indicating its foreign origin. The opinion from China, Japan and India." ofElgood (1951; personal communication, 1962) that A leading article in the British Medical Journal syphilis first appeared in Persia at the beginning of the (1962) typifies the confusion and lack of precision. sixteenth centuryisbased uponwidepersonalexamina- It states that " syphilis continues to be the most tion of original texts. However, as far as syphilis in controversial disease of all, there still being in- Europe is concerned, the evidence for its origin in adequate material to prove conclusively whether it America is neither impressive nor precise. The history originated in the New World or the Old". Later it of venereal syphilis in Asia needs further study. is suggested that " there is, in fact, no good reason The other explanation (Buret, 1895; Sudhoff, 1925; why both continents should not have been affected Holcomb, 1940; Castiglione, 1947; Campbell, 1954; during pre-Columbian times ",1 but no good reason Singer & Underwood, 1962) is that venereal syphilis is given why they should. was present in Europe but was not identified from I The possibility that venereal syphilis was brought to among a number of diseases, including some epi- Europe by invaders from Asia in the thirteenth century demic diseases, referred to en masse as " leprosy ". needs investigation. Rat (1891) says that if syphilis did not originate in Europe, it might have been brought to Spain They speak of the alleged venereal transmission of from Africa by the Moors. The last Moorish kingdom in this " leprosy " which disappeared from writings Spain (Granada) did not surrender until 1492. ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 29

Bones with allegedly venereal syphilitic changes of delayed condylomatous relapses might provide have been found in cemeteries near former leprosy the opportunity for venereal transmission to un- institutions. The question has also been raised why infected and susceptible partners. Guthe & Luger mercury, one of the first effective substances used in (1957) suggest this change in Syria. Denser settle- the treatment of venereal syphilis, was of such high ment, more clothing and increasing sexual laxity as repute in Europe during the first fifteen centuries of well as decreasing endemic syphilis might well have the Christian era, if there were no venereal syphilis. assisted climatic change in the selection of mutants The significance of the apparent absence of syphilitic towards venereal syphilis treponemes. bone lesions in Europe during this period still re- Davies (1956) has suggested that venereal syphilis mains to be understood. was introduced into the lake areas of Uganda in the Some writers think that the epidemic of Naples last half of the nineteenth century and since the turn in 1493, like others before it, was not due to venereal of the century has replaced an already existing ende- syphilis but to an outbreak of one of the epidemic mic syphilis. The increase in the amount of clothing communicable diseases that are known today. Others worn in these districts during the present century have pointed out that the American origin of the may have hastened this. However, the change, " Naples epidemic " was not raised until 25 years which would accompany the improvement of stand- after Columbus's return. ards of living, might rather have been the reduction In considering the absence of clear descriptions of of non-venereally transmitted venereal syphilis. The syphilis before the early years of the sixteenth cen- affected population made up an organized kingdom tury one should remember that syphilis and gono- in contrast to the organizational disorder of their rrhoea were not generally recognized as separate relatively naked neighbours among whom yaws was diseases until the second half of the eighteenth cen- highly endemic (Hackett, 1947). It has been pointed tury (Bell in 1793). Even such an able investigator out already that the climate of the affected province, as John Hunter (1728-1793) did not accept this and Buganda, is not arid or semi-arid but humid. carried out an experiment upon himself by which he If endemic syphilis was in Buganda, how it came erroneously satisfied himself that they were the same is unknown. There is the same problem of venereal disease. Locomotor ataxia (tabes dorsalis) was not syphilis in Ethiopia, where it may have been intro- clearly described in the medical literature (Duchenne duced by visitors, slavers or other traders. in 1858) nor its syphilitic.origin recognized (Fournier The change to venereal transmission might have in 1876) until the nineteenth century, although in its occurred with the growth of big cities, together with later stages it can be readily diagnosed at a distance increased clothing, in the now arid countries of the by the gait of the sufferer. McGeoch (1960) reports ,eastern Mediterranean and south-western Asia that no reference to neurosyphilis has been recog- (Map 6). This might have been about 3000 B.C. nized in the writings of Shakespeare (1564-1616). during the post-glacial climatic optimum which Therefore, before and for some time after the fif- culminated between 5000 B.C. and 2500 B.C., when teenth century the diagnosis of syphilis doubtless the climatic zones were displaced towards the higher included many conditions, for example, some forms latitudes and temporarily the equatorial/monsoon of leprosy and some skin diseases now known not belts were widened and the desert zones less severe. to be syphilitic. Something similar happened a However, from about 3000 B.C. desiccation of the generation ago with " influenza ", which was a previously arid areas returned and has remained generic rather than a specific diagnosis before ever since (Brooks, 1949; Lamb, 1963) and was laboratory methods for diagnosis were developed. probably maximal during the twentieth century. This third and last suggested step in the evolution Venereal syphilis was probably carried to the of the treponematoses would involve the change Mediterranean littoral by shipping and later through- from a non-venereal disease (endemic syphilis) of out Europe, which was a treponemally uncommitted rural children to a venereal disease (venereal syphi- area, especially after the first century B.C. with the lis) of urban adults. This might begin with the Roman conquests. In rural populations in Syria, decrease of childhood infections because venereal Saudi Arabia, Iran and Iraq the indigenous trepone- transmission would not be expected in a population matosis is still endemic syphilis. In rural Syria infected and immunized in childhood. If endemic (Hudson, 1946) venereal syphilis was known as syphilis from childhood infection decreased more franji, meaning " foreigner ". This is also reported adults would be susceptible and a few " last cases " of parts of India (Reddy, 1936). The absence of

3 30 C. J. HACKETr lesions resembling those of venereal syphilis in bones syphilis than to yaws its origin from the former in Europe before the end of the fifteenth century seems likely. Probably yaws was not present in the and in early Egyptian burials (Rowling, 1961) needs Americas when Columbus arrived; pinta is the an- careful consideration. However, the disease which, cient American endemic treponematosis. Venereal it is here suggested, evolved from endemic syphilis syphilis was said to have been unknown in North about 3000 B.C., may have still been a " mild " one, Canadian Indians before European contacts (Hol- until a mutant appeared at the end of the fifteenth comb, 1940) and the limited studies of Medina (1954) century in Europe which caused a more grave of the resistance of pinta patients to the yaws disease (Shrewsbury, quoted by Harrison, 1959; treponeme would suggest possible resistance to and Med. J. Aust., 1961). syphilis. This in turn is further though weak The social conditions, customs and habits of the support for the absence of syphilis in the Ameri- congested urban populations of Europe in the cas. fifteenth and sixteenth centuries (Taylor, 1953) would As stated above, it is suggested here that in cities, have assisted in spreading venereal syphilis both perhaps in the eastern Mediterranean or south-west non-venereally and venereally. Venereal syphilis in Asia, conditions developed which favoured trepo- Europe is generally supposed to have become less neme mutants tending towards venereal syphilis. destructive since its first recognition at the end of the This resulted in the replacement of endemic syphilis fifteenth century. At present venereal syphilis is by venereal syphilis in urban populations, and later regarded as being more gummatous in patients of Europe became gradually but finally generally African descent (in America) and more neuro- infected. Thence it or a further mutant causing a pathogenic in patients of European stock. However, grave disease was probably carried during and after T. pallidum of venereal syphilis appears to be a fairly the sixteenth century to the Americas, southern uniform species. Any variations in its clinical Africa (Sax, 1952), India, south Asian countries, manifestations might have been due to other than China and Australia (Map 7) (see page 28). treponemal factors. Dr H. H. Lamb of the Meteorological Office, One of Hudson's (1958) conclusions is that yaws Bracknell, Berks., England (personal communica- arose in Africa from a saprophytic treponeme tion, 1962) has pointed out that in Europe during several hundred thousand years ago and spread the fifteenth century the climate was deteriorating eastwards to India and Oceania about 100 000 years (cooling)-in some decades, particularly in the ago. He also thinks yaws extended into America. 1430s and 1490s, deteriorating sharply-though it As yaws left the tropics and entered cooler climates temporarily recovered somewhat between 1500 and it became, he says, endemic syphilis and about 1550. The fifteenth century was one of consider- 10 000 years ago in towns and cities on the Nile and able difficulty for the rural people, particularly Mesopotamia it became venereal syphilis. of northern Europe, because of the worsening Hudson (1962) at the end of an assessment of of the climate and the grave results of the Black las buvas of Villalobos (1472-1556) states: Death. " It is more likely that in the latter decades of the fifteenth century the venereal form of syphilis was coming to be recognized as it emerged from a widely disseminated CONCLUSION non-venereal endemic form of the disease in Europe. The process of transition in the epidemiology of syphilis A brief review of the causal organisms, clinical from non-venereal to venereal, and endemic to sporadic, course, epidemiology, estimated geographical dis- had been going on in that continent for many years before 1493. Columbus could have had nothing to do tribution at the beginning of the present (Map 1) with it ". and of the sixteenth centuries (Map 2) and several other aspects relevant to the origin of the four Cockburn (1961) presents ideas of a " philoso- human treponematoses shows that much more phical nature" about the characteristics and origin knowledge is needed before a definitive statement of the treponematoses, and Willcox (1960) stresses about this can be made. However, indications can environmental factors in the " evolutionary cycle be given as to where steps should be taken or investi- of the treponematoses ". gations made, before it is too late, which will assist Since venereal syphilis is geographically and in the ultimate solution of these interesting and not pathologically more closely related to endemic unimportant questions. ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 31

L6

uJ z

0

w U ) :.. ..: 0 I-~~~~~~~~~~~~~~~~~~~~~~~~I 0~~~~~~~~~~~~~~~~~~~~~~~~0 wL LU~~~~~~~~~~~~

0~~~~~~~~~~~~~

z 0 m

U)

4,)

0.0 0 CD ~~~~~~~~~~~~~~~~~~~~0 0~~~~~~~~~~~~~~~~~~~~~~

CL 32 C. J. HACKETT

00 z 0 z

x ILl z Lu z LU 'u

IL

LU0

mLU

U)

-i 0~

z 0

.(U*

zI LUO

IL

-J

LUw IL C 0 LU a) 0-J

0 0 IL CL o ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 33

'4

0

Lim 8id§ I- 0I- m co, 0

co U. z

x LU LU -j 0 m

0~(L

L6r-

o

0a

04 CQ 0

0 0

C'i 34 C. J. HACKETT

m ff% r4 en 0 im

C) m 0 0 0

0

I-

0 0L a- z zJ m

0 zI- U. z CL z H:I--x LU LU -J 0 0.

Ui

CDo am CL0

0

0 a)

a) 4) ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 35

LU

IL~~~~~~~~~~~~~~~~~~~~~~~~~~~L

U

0 0

0. CZ

a.UC

4:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~0 36 C. J. HACKETT

* M

z LU -I.

I- Co0x 0 LU zLu o

Lu

IL mIL

0:d 0 L-8 LUU I- *>

-J

0 yu

LIU 0 0:- :: z 0,::: :::::: LU en

II C- ~Lu z

Co I Co I- Luz a) 0 0 U)0 Lu E O. 08 z

a)

-J Co ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 37

o) M

J '-4 "4

LU

LU LI) Iz LU ()o

Z I * O LUL 0 0F -O 7- Z-0>- UI) O u U

z LU I-- a. 0

0.LU «

01-LU I O (D

OIg 4 Z z 7- ui zO

0 OL 0 CL

0U 0 o4

a.LUO 0 Cl~ 0 co co CO ui0 C~

0 04 1- 0) c0 LU 0. U) W.a.) D3 38 C. J. HACKETIr

It is suggested that: treponeme mutants nor to hazard what characters 1. Pinta probably arose in the Afro-Asian land they might possess. mass from an animal infection and by about 15 000 Much more information is needed. One of the B.C. had spread throughout the world (Map 3). It most obvious and urgent needs is the collection of later became isolated in the Americas. an adequate and carefully selected representative series of treponemal strains in readiness for the time 2. Yaws arose in the Afro-Asian land mass from when full antigenic studies of treponemes can be mutants of the pinta treponeme and by about made. Already it may be too late to do this for the 10 000 B.C. had spread throughout the world, but Australian endemic treponematoses. In a very few did not reach the Americas, which were then isolated years it may well be too late to attempt to make by the flooding of the Bering Strait with the melting a useful collection of such strains elsewhere. Then of the polar ice-caps towards the end of the last not only will an important contribution to the study glaciation (Map 4). and history of human disease be lost but so will 3. Endemic syphilis arose from yaws about information about the migrations of man long ago. 7000 B.C. when arid climates following the retreat The elucidation of the origin of the treponematoses of the last glaciation favoured the selection of might be of importance in the eradication of vene- suitable treponemes (Map 5). real syphilis. 4. Venereal syphilis evolved from endemic syphilis A careful study is needed of bones from accurately about 3000 B.C., when big cities developed in south- dated burials throughout the world before the end western Asia during the post-glacial climatic of the fifteenth century. This must start with an optimum which produced conditions favouring the attempt to define the criteria for the recognition of selection of suitable mutants (Map 6); later (after changes due to treponematoses and other diseases the first century B.C.) it spread throughout Europe. likely to have been present in ancient times. The This was probably a " mild " disease until a muta- possibility of finding antibodies to treponemes in tion towards the end of the fifteenth century A.D. pre-Columbian material might be studied (Durel, may have given rise in Europe to the syphilis of the quoted by Harrison, 1959). To know if syphilitic, or present. rather treponemal, lesions occur in pre-Columbian bones in Europe or America-or in both or in 5. Venereal syphilis was carried to the trepone- neither-would be of great interest. There are mally uncommitted populations of the world with already suspicions that some of the lesions of the European expansion of the sixteenth and sub- European bones of long ago may result more from -sequent centuries (Map 7). excessive treatment with mercury than from infec- The proposed order of the events is more probable tious disease. and important than the dates suggested. However, A search for further animal treponematoses by with more knowledge both may be changed. This the examination of sera for antibodies might be is not the occasion to consider the changing con- combined with other studies on wild animals which ditions of the present which might favour further are going on in various tropical countries.

RItSUMt L'origine des treponematoses, que l'auteur tente de dernire periode glaciaire, s'est trouvee cantonnee sur le retracer, reste en grande partie conjecturale. Ce que l'on continent americain. sait de l'evolution clinique, de la repartition geographique 2. Vers 10 000 av. J.-C., des conditions de milieu ont et epidemiologique des quatre treponematoses humaines peut-etre favorise des mutations du treponeme, mutations (syphilis venerienne, syphilis endemique, pian et pinta) responsables du pian, largement repandu a travers l'Asie qui semblent 6troitement apparentees, montre la necessite et l'Afrique. d'etudes plus poussees, dans le present et le passe, pour 3. Vers 7000 av. J.-C., le climat aride ayant succede a preciser leur developpement. la derniere grande glaciation a favorise les mutations qui Les connaissances actuelles, pour imparfaites qu'elles ont, secondairement, determine l'eclosion de la syphilis soient, peuvent donner lieu aux hypotheses suivantes: endemique. 1. Vers 15 000 av. J.-C., la pinta, d'origine probable- 4. Vers 3000 av. J.-C. la naissance, dans l'Asie du ment animale, s'est repandue a travers le monde, mais a Sud-Ouest, de grandes villes sous le meilleur climat post- la suite du creusement du detroit de Behring a la fin de la glaciaire a produit des conditions favorables La la selection ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 39 de mutants responsables de la syphilis venerienne; c'est deliberement choisies; on devrait egalement' rechercher aprEs le ler siecle de notre ere que la maladie s'est etendue soigneusement d'autres treponematoses de l'animal (en a toute l'Europe. plus de celle du lapin, dejia connue), cela en attendant 5. A la fin du XVe siecle une nouvelle mutation peut d'avoir de meilleures methodes d'etudes. I1 faut avoir des avoir fait de la syphilis venerienne la maladie grave que connaissances plus etendues et plus precises sur la fre- nous connaissons maintenant. quence et la distribution geographique des lesions trepo- 6. Pendant le XVIe siecle et depuis lors la maladie a nemateuses des os trouves dans les tombeaux precolom- ete transportee du fait des explorations et de l'expansion biens des Ameriques ainsi que dans plusieurs autres geographique aux contrees indemnes de treponematoses. parties du monde. Des confusions entre syphilis vene- On devrait recueillir, pendant qu'il en est encore rienne et pian, faites par les premiers explorateurs dans temps, des treponemes provenant de parties du monde leurs journaux de voyage, se retrouvent dans les musees.

REFERENCES Akrawi, F. (1949) Brit. J. vener. Dis., 25, 115 Castello, V. P. & Castanedo, C. (1952) Pinta or carate. Baermann, G. (1911) Arch. Schiffs- u. Tropenhyg., 15, In: Simons, R. D. G. P., ed., Handbook of tropical Suppl. 6, p. 335 dermatology and medical mycology, Amsterdam, Bancroft, E. (1769) An essay on the natural history of Elsevier, p. 305 Guiana, London, p. 385 Castiglioni, A. (1947) A history of medicine, 2nd ed., Barnard, C. C. (1952) J. trop. Med. Hyg., 55, 100, 132 New York, Knopf, p. 543 Basedow, H. (1932) J. trop. Med. Hyg., 35, 274 Charlouis, M. (1897) On polypapilloma tropicum (fram- Bechelli, L. M. (1954) Rev. bras. Leprol., 22, 157 boesia). In: Selected essays and monographs, London, Black, E. C. & Cleland, J. B. (1938) J. trop. Med. Hyg., New Sydenham Society, p. 285 41, 69 Cleland, J. B. (1928) J. trop. Med. Hyg., 31, 141, 202 Blacklock, D. B. (1932a) Ann. trop. Med. Hyg., 26, 423 Cockburn, T. A. (1961) Bull. Wld Hlth Org., 24, 221 Blacklock, D. B. (1932b) Trop. Dis. Bull., 30, 739 Cole, N. H., Harkin, J. C., Kraus, B. S. & Moritz, A. R. Bloch, I. (19C8) History of syphilis. In: Power, D'A. & (1955) A.M.A. Arch. Derm., 71, 231 Murphy, J. K., ed., A system of syphilis, London, Cook, C. E. (1949) Med. J. Aust., 1, 569 Hodder & Stoughton, p. 1 Darlington, P. J. (1957) Zoogeography, New York, Wiley, Botreau-Roussel, J. M. (1925) Osteites pianiques ( Goun- pp. 555-556, 571, 576 doti >, Paris, Masson Davies, J. N. P. (1956) Bull. Wld Hlth Org., 15, 1041 Botreau-Roussel, J. M. (1961) Bull. Soc. Path. exot., Eagle, H. (1948) The spirochetes. In: Dubos, R., ed., 54, 177 Bacterial and myotic infections in man, Philadelphia, Botreau-Roussel, J. M. (1962) Bull. Soc. Path. exot., Lippincott, p. 532 55, 228 Eckstein, 0. (1928) Bull. Soc. med. Hist. Chicago, 4, 71 Brit. med. J., 1962, 1, 852 Edmundson, W. F., Rico, A. L. & Olansky, S. (1953) Brooks, C. E. P. (1949) Climate through the ages, London, Amer. J. Syph., 37, 207, 213 Ernest Benn Eisenberg, H., Plotke, F. & Baker, A. H. (1949) J. vener. Bruijn, J. H. de (1961) Antonie v. Leeuwenhoek, 24, 98 Dis. Inform., 30, 7 Buret, F. (1895) Syphilis today and among the ancients, Elgood, C. (1951) A medical history ofPersia, Cambridge, Philadelphia, vol. 2, p. 113 University Press Burnet, F. M. (1960) Principles of animal virology, 2nd Fenner, F. J. (1950) Med. J. Aust., 2, 813 ed., New York, Academic Press p. 388 Ferris, H. W. & Turner, T. B. (1937) Arch. Path. (Chi- Burnet, F. M. (1962) Natural history ofinfectious diseases, cago), 24, 703 3rd ed., Cambridge, University Press Ferris, H. W. & Turner, T. B. (1938) Arch. Path. (Chi- Buxton, P. A. (1928) Researches in Polynesia and Melane- cago), 26, 491 sia. Parts V-VII, London, p. 83 (Memoir Series of the Festenstein, H. & Bokkenheuser, V. (1961) Brit. J. exp. London School of Hygiene and Tropical Medicine, Path., 62, 158 No. 2) Fitzgerald, G. H. & Dey, N. C. (1931) Indian med. Gaz., Campbell, D. J. (1954) The venereal diseases. In: Bett, 66, 125 W. R., ed., The history and conquest ofcommon diseases, Fournier, A. (1903) Prophylaxie de la syphilis, Paris, Norman, University of Oklahoma Press, p. 178 p. 217 Capper, A. (1925) Arch. Derm. Syph. (Chicago), 12, 509 Furtado, T.A. (1955) Manifesta!poes tardias daframboesia, Castellani, A. (1908) Framboesia tropica (yaws, pian, Belo Horizonte (Thesis), p. 249 bouba). In: Transactions of the Sixth International Gjestland, T. (1955) The Oslo study of untreated syphilis, Dermatological Congress, 1907, New York, vol. 2, Oslo, Akademisk Forlag (Acta derm.-venereol. p. 616 (Stockh.), 35, Suppl. 34) 40 C. J. HACKETT

Gladstone, G. P. & Heyningen, W. E. van (1962) Patho- Hirsch, A. (1885) Handbook ofgeographical and historical genicity and virulence of micro-organisms. In: Florey, pathology, London, New Sydenham Society, vol. 2, H., ed., Generalpathology, London, Lloyd-Luke, p. 723 p. 59 Grin, E. I. (1953) Epidemiology and control of endemic Holcomb, R. C. (1934) U.S. nav. med. Bull., 32, 401 syphilis, Geneva (World Health Organization: Mono- Holcomb, R. C. (1940) U.S. nav. med. Bull., 38, 177 graph Series, No. 11) Hrdlifka, A. (1932) J. Amer. med. Ass., 99, 1661 Grin, E. I. (1961) Bull. Wld Hlth Org., 24, 229 Hudson, E. H. (1936) Ann. trop. Med. Parasit., 30, 3 Gron, K. (1928) Syphilis-Endemien. In: Jadassohn, J., Hudson, E. H. (1937) Trans. roy. Soc. trop. Med. Hyg., ed., Handbuch der Haut- und Geschlechtskrankheiten, 31, 9 Berlin, vol. 17, part 3, p. 285 Hudson, E. H. (1946) Treponematosis, New York, Ox- GuimarRes, F. N. (1946) Mem. Inst. Osw. Cruz. 44, 649 ford Loos--leaf Medicine Guimar,es, F. N. & Roderigues, B. A. (1948) Mem. Inst. Hudson, E. H. (1958) Non-venereal syphilis, Edinburgh Osw. Cruz, 46, 135 & London, Livingstone Guthe, T. & Luger, A. (1957) Dermatologica (Basel), Hudson, E. H. (1962) Amer. J. Med., 32, 578 115, 248 Hume, J. (1744) A description of the African distemper Haag, W. G. (1962) Sci. Amer., 206, 112 called the yaws, with the true method of cure. In: Hackett, C. J. (1936a) Boomerang leg and yaws in Aus- Medical essays and observations, Edinburgh, vol. 5, tralian aborigines, London (Royal Society of Tropical Part 2, p. 787 Medicine and Hygiene, Monograph No. 1) Hutchinson, J. (1908) Introduction. In: Power, D'A. & Hackett, C. J. (1936b) Med. J. Aust., 1, 733 Murphy, J. K., ed., A system of syphilis, London, Hackett, C. J. (1939) Trans. roy. Soc. trop. Med. Hyg., Hodder & Stoughton, p. xxiv 32, 429 Jeans, A. B. & Cook, J. V. (1930) Clin. Pediat., 17, 131, Hackett, C. J. (1946) Trans. roy. Soc. trop. Med. Hyg., 152, 233 40, 206 Kranendonk, 0. J. M. (1958) Serological and epidemio- Hackett, C. J. (1947) Brit. med. J., 1, 88 logical aspects in yaws control, Amsterdam (Thesis) Hackett, C. J. (1951) Bone lesions of yaws in Uganda, Kynsey, W. R. (1881) Report on the " parangi disease" Oxford, Blackwell of Ceylon, Colombo Hackett, C. J. (1953) Extent and nature of the yaws Lacapere, G. (1923) La syphilis arabe (Maroc, Algerie, problem in Africa. In: First International Symposium Tunisie), Paris, Doin on Yaws Control, Geneva, p. 129 (World Health Lamb, H. H. (1963) On the nature of certain climatic Organization: Monograph Series, No. 15) epochs which differed from the modern (1900-1939) Hackett, C. J. (1957a) An international nomenclature of normal. In: Changes of climate. Proceedings of the yaws lesions, Geneva (World Health Organization: Rome symposium organised by UNESCO and WMO, Monograph Series, No. 36) Paris, UNESCO, p. 125 Hackett, C. J. (1957b) J. trop. Med. Hyg., 60, 159 Lambert, S. L. (1931) Oceania, 2, 163 Hackett, C. J. (1959) J. trop. Med. Hyg., 62, 153 Lancereaux, E. (1868) A treatise on syphilis, London, Hackett, C. J. (1960) Bull. Wld Hlth Org., 23, 739 New Sydenham Society, vol. 1, p. 60 Hackett, C. J. & Guthe, T. (1956) Bull. Wld Hlth Org., Lawrence, E. (1941) Med. Press, 205, 300 15, 869 Limbos, P. (1957) Arch. belge Derm Syph., 12, 392 Hackett, C. J. & Loewenthal, L. J. A. (1960) Differential Lopez-Rizal, L. & Sellards, A. W. (1926) Philipp. J. Sci., diagnosis of yaws, Geneva (World Health Organiza- 30, 497 tion: Monograph Series, No. 45) Luger, A. (1958) Derm. Wschr., 137, 25, 57 Hallenberger, 0. (1916) Arch. Schifs- u. Tropenhyg., 20, Luger, A. & Schmid, E. E. (1961) Derm. Wschr., 143, 617 Suppl. 3, pp. 168, 175 Lwoff, H. (1959) Bact. Rev., 23, 109 Hamlyn, H. (1939) Yale J. Biol. Med., 12, 29 McElligott, G. L. M. (1960) Brit. J. vener. Dis., 34, 207 Harding, R. D. (1949) Trans. roy. Soc. trop. Med. Hyg., McGeoch, A. (1960) Med. J. Aust., 1, 348 42, 348 MacKay, C. V. (1938) Med. J. Aust., 2, 537 Harrison, L. W. (1959) Brit. J. vener. Dis., 35, 1 McLeod, C. & Turner, T. B. (1946) Amer. J. Syph., Hartmann, G. (1956) An epidemiological study of the 30, 442 import ofsyphilis into, diffusion within, and export from Magnuson, H. J., Eagle, H. & Fleischman, R. (1948) Copenhagen. In: Maritime venereal-disease control, Amer. J. Syph., 32, 1 Geneva, WHO Regional Office for Europe, p. 111 Magnuson, H. J. & Rosenau, B. J. (1948) Amer. J. (limited distribution) Syph., 32, 418 Hasselmann, M. (1931) China med. J., 45, 1131 Magnuson, H. J., Thomas, E. W., Olansky, S., Kaplan, Hasselmann, M. (1957) Brit. J. vener. Dis., 33, 5 B. I., Dc Mello, L. & Cutler, J. C. (1956) Medicine Herrej6n, S. G. (1938) El mal del pinto, Leverkusen, Baltimore), 35, 33 Bayer Manson, P. (1898) Tropical diseases; a manual of the Hill, M. & Mugge, R. (1954) Amer. J. Syph., 38, 583 diseases of warm countries, London, Cassel, p. 423 ON THE ORIGIN OF THE HUMAN TREPONEMATOSES 41

Mathew, W. D. (1939) Climate and evolution, New York, Schobl, 0. (1928) Philipp. J. Sci., 35, 209 New York Academy of Sciences, p. 93 Schobl, 0. & Hasselmann, M. (1932) Arch. Schiffs.- u. Marquez, F., Rein, C. R. & Arias, 0. (1955) Bull. Wld Tropenhyg., 36, Suppl. 2, p. 109 Hlth Org., 13, 299 Scott, H. H. (1939) A history oftropical medicine, London, Marshall, I. D. (1959) J. Hyg. (Lond.), 57, 484 Arnold, vol. 2, p. 999 Maxwell, J. L. (1916) J. trop. Med. Hyg., 19, 237 Scott, H. H. (1943) Trans. roy. Soc. trop. Med. Hyg., 37, Med. J. Aust., 1961, 2, 603 169 Medina, R. (1954) Arch. venez. Pat. trop., 2, 5 Senecal, J., Aubry, L. & Falade, S. (1962) W. Afr. med. J., Medina, R. (1959) Arch. venez, Pat. trop., 3, 290 11, 93 M6lbert, E. (1956) Z. Hyg. Infekt.-Kr., 142, 510 Silverstein, A. M. (1962) Nature (Lond.), 194, 196 M0ller-Christensen, V. (1961) Bone changes in leprosy, Singer, C. J. & Underwood, E. A. (1962) A short history Copenhagen, Munksgaard ofmedicine, 2nd ed., Oxford, Clarendon Press, pp. 106, Moseley, B. (1800) Medical tracts, 2nd ed., London, 108 p. 184 Sosa-Martinez, J. & Peralta, S. (1961) Amer. J trop. Med. Mourant, A. E., Kopec, A. C. & Domaniewska-Sobczak, Hyg., 10, 556 K. (1958) The AMO bloodgroups; comprehensive tables Spittel, R. L. (1923) Framboesia tropica (parangi of and maps of world distribution, Oxford, Blackwell Ceylon), London. Bailliere, Tindall and Cox Murray, J. F., Merriweather, A. M., Freedman, M. J. Stannus, H. S. (1926) Trop. Dis. Bull., 23, 181 & Villiers, D. J. de (1956) Bull. Wld Hlth Org., 15, 975 Stannus, H. S. (1936) Yaws-syphilis. In: Empire Social Nicholls, H. A. H. (1899) In: Twentieth century practice Hygiene Handbook, London, Allen & Unwin, p. 577 ofmedicine, New York, William Wood & Co., vol. 16, Stewart, T. D. & Spoehr, A. (1952) Bull. Hist. Med., 26, p. 305 538 Nitsen, R. van (1944) Mem. Inst. colon. belge Sci. nat., Sudhoff, K. F. J. (1925) The earliest printed literature on 13, No. 7 syphilis. Being ten tractates from the years 1495-1498, Olansky, S. & Price, I. N. 0. (1956) Bull. Wld Hlth Org., Florence, R. Lier.& Co. 14,249 Swain, R. H. A. (1955) J. path. Bact., 69, 117 Platt, B. S. (1958) Trans. roy. Soc. trop. Med. Hyg., Swediaur, F. (1821) Venereal or syphilitic diseases, 52, 189 London, pp. 285, 292, 297 Pollock, J. S. M. (1953) Trans. roy. Soc. trop. Med. Hyg., Takahashi, S. (1939) Acta jap. med. trop., 1, 57 47, 431 Taylor, G. R. (1953) Sex in history, London, Thames Powell, A. (1923) Proc. roy. Soc. Med., 16, part 3, p. 15 Taylor, W. N. (1954) S. Afr. med. J., 28, 176 Power, D'A. (1934) In: Bett, W. R., ed., A short history Tindale, N. B. (1960) Colorado Quart., 8, 229 of some common diseases, London, Oxford University Tucker, H. A. & Mulheim, J. E. (1948) Amer. J. Syph., Press, p. 34 32, 345 Rajam, R. V., Rangiah, P. N. & Sowmini, C. N. (1955) Turner, T. B. (1937) Amer. J. Hyg., 25, 477 Indian J. Derm. Venereol., 21, 117 Turner, T. B. & Hollander, D. H. (1957) Biology of the Ramsay, C. G. (1925) J. trop. Med. Hyg., 28, 85 treponematoses, Geneva (World Health Organization: Ramsay, C. G. (1927) Trans. roy. Soc. trop. Med. Hyg., Monograph Series, No. 35) 20, 506 Veldkamp, H. (1960) Antonie v. Leeuwenhoek, 26, 102 Rat, J. N. (1891) Yaws: its nature and treatment, London, Weller, C. V. (1937) Amer. J. Syph., 21, 357 Waterlow, p. 41 Willcox, R. R. (1960) Brit. J. vener. Dis., 36, 78 Reddy, D. V. S. (1936) Indian J. vener. Dis., 2, 103 Willett, H. C. (1953) Atmospheric and oceanic circulation Rost, G. S. (1942) Radiology, 38, 320 as factors in glacial-interglacial changes of climate. Rowling, J. T. (1961) Proc. roy. Soc. Med., 54, 409 In: Shapley, H., ed., Climatic change, Cambridge, Samwell, D. (1786) A narrative of the death of Captain Mass., Harvard University Press James Cook, to which are added some particulars con- Williams, H. U. (1932) Arch. Path. (Chicago), 13, 779, 931 cerning his life and character and observations respecting Williams, H. U. (1936) Arch. Derm. Syph., 33, 783 the introduction ofthe venereal disease into the Sandwich Wong, K. C. (1918) China med. J., 22, 349 Islands, London, Robinson Yasuyama, K. (1928) Philipp. J. Sci., 35, 333 Sanchez, F. G., Mazzotti, L. & Salenas, E. G. (1961) Yu, K. Y. (1957) China med. J., 75, 616 Saludpubl. Mex., 3, 183 Zeuner, F. E. (1958) Dating the past, 4th ed., London, Sax, S. (1952) S. Afr. med. J., 26, 1037 Methuen, p. 282